Pyridin-2-one derivatives of formula (III) useful as EP3 receptor antagonists

ABSTRACT

The present invention is directed to pyridin-2-one derivatives, pharmaceutical compositions containing them and their use as antagonists of the EP3 receptor, for the treatment of for example, impaired oral glucose tolerance, elevated fasting glucose, Type II Diabetes Mellitus, Syndrome X (also known as Metabolic Syndrome) and related disorders and complications thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application claims priority to U.S. Provisional Patent ApplicationNo. 62/543,458, filed Aug. 10, 2017, the disclosure of which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to pyridin-2-one derivatives,pharmaceutical compositions containing them and their use as antagonistsof the EP3 receptor, for the treatment of for example, impaired oralglucose tolerance, elevated fasting glucose, Type II Diabetes Mellitus,Syndrome X (also known as Metabolic Syndrome) and related disorders andcomplications thereof.

BACKGROUND OF THE INVENTION

Type I diabetes represents about 5-10% of all diabetes cases and occursas a result of destruction of the pancreatic beta cells, which producethe hormone insulin, by the body's own immune system. The patients arecompletely dependent on insulin treatment for survival. Type II diabetesis more common (90-95% of all cases). It starts as insulin resistanceparticularly in the cells of liver, muscle, and adipose tissue thatbecome resistant to the effects of insulin in stimulating glucose andlipid metabolism. As the disease progresses the pancreas gradually losesits ability to produce insulin and if not properly controlled withmedication it may lead to pancreatic β-cell failure requiring completedependence on insulin. While there are five different categories of TypeII diabetes medications, they may be ineffective and/or causeundesirable adverse effects such as hypoglycemia, gastrointestinaldisturbances, lactic acidosis, weight gain, edema, and anemia.

There continues to be a need to introduce new effective treatments thatmay be used less frequently, preferably causing fewer side effects andcan act either by increasing the endogenous insulin secretion orindependently from the actions of insulin.

Prostanoid receptors consist of EP, FP, IP, TP and DP receptors. The EPreceptor family is divided into four distinct subtypes EP1, EP2, EP3 andEP4. The EP3 receptor is a 7-transmembrane G-protein coupled receptorfound in various human tissues including the kidney, uterus, bladder,stomach and brain. Prostaglandin E2 (PGE2), a primary product ofarachidonic acid metabolism by the cyclooxygenase pathway, is thenatural ligand of EP3 as well as other EP receptor subtypes. Clinicalstudies have provided strong evidence of the role of increased levels ofPGE2 as a contributor to defective insulin secretion in diabeticpatients. Recently, the functional link between PGE2 suppression ofglucose-stimulated insulin secretion (GSIS) and the EP3 receptor wasconfirmed using β-cell lines and isolated islets. It is hypothesizedthat increased PGE2 signaling through the EP3 receptor might becoincident with the development of diabetes and contribute to β-celldysfunction. Therefore, EP3 receptor antagonists, may be an effectivetreatment for Type I and Type II Diabetes Mellitus, by relieving theinhibitory action of PGE2 to partially restore defective GSIS indiabetic patients. EP3 receptor antagonists may also be useful for thetreatment of bladder over-activity, cerebrovascular disease, coronaryartery disease, hypertension, neurodegenerative disorders, pain,premature labor, restenosis, thrombosis and colon cancer (KAWAMORI, T.,et al., “Prostanoid receptors and colon carcinogenesis”, Carcinogenesisand Modification of Carcinogenesis (2005), pp 243-251.).

JIN, J., et al., in ACS Med. Chem. Lett., 2010, pp 316-320, Vol. 1describe novel 3-oxazolidinedione-6-aryl pyridinones as potent,selective and orally active EP3 receptor antagonists. MORALES-RAMOS, A.I., et al., in Biororg & Med Chem Lett., 2011, pp 2806-2811, Vol. 21describe structure-activity relationship studies of novel3-oxazolidinedione-6-naphthyl-2-pyridinones as potent and orallyavailable EP3 receptor antagonists.

BAHNCK, K., et al., in US Patent Publication 2016/0176851 A1 (PublishedJun. 23, 2016) and BAHNCK, K., et al., in US Patent Publication2015/0099782 A1 (Published Apr. 9, 2015) describe antagonists ofprostaglandin EP3 receptor.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein

is selected from the group consisting of naphth-2-yl, indol-5-yl,indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl,benzothiazol-5-yl, benzothiazol-6-yl, benzoisothiazol-6-yl,chroman-7-yl, chromen-7-yl, benzo[d][1,3]dioxol-5-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl and2,3-dihydro-benzo[b][1,4]dioxin-6-yl;

wherein the naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl,benzimidazol-5-yl, benzimidazol-6-yl, benzothiazol-5-yl,benzothiazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl,benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl; is optionally substituted on thephenyl portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, cyano, C₁₋₃alkyl, fluorinatedC₁₋₂alkyl, C₁₋₃alkoxy, fluorinated C₁₋₂alkoxy and C₃₋₆cycloalkyl;

and wherein the naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl,benzimidazol-5-yl, benzimidazol-6-yl, benzothiazol-5-yl,benzothiazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl,benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl; is further optionally substitutedon the

portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, cyano, C₁₋₃alkyl, fluorinatedC₁₋₂alkyl, C₁₋₃alkoxy, fluorinated C₁₋₂alkoxy and C₃₋₆cycloalkyl;

R¹ is selected from the group consisting of hydrogen, halogen andC₁₋₄alkyl;

R² is selected from the group consisting of hydrogen, halogen andC₁₋₄alkyl;

—X

is selected from the group consisting of —CR^(A)R^(B)—,—CR^(A)R^(B)—CH₂—, CH₂—CHR^(C)—, —CR^(A)R^(B)—CR^(C)═, —C(R^(A))═,—CR^(A)R^(B)—N(R^(D))—, —CR^(A)R^(B)—CH₂—N(R^(D))—,—CR^(A)R^(B)—C(O)—N(R^(D))—, —CR^(A)R^(B)—CH₂—C(O)—N(R^(D))—,—CR^(A)R^(B)—C(O)—N(R^(D))—SO₂—, —CR^(A)R^(B)—CH₂—C(O)—N(R^(D))—SO₂—,—CR^(A)R^(B)—N(R^(D))—SO₂—, —CR^(A)R^(B)—CH₂—N(R^(D))—SO₂, and—CR^(A)R^(B)—CH₂—SO₂—; wherein the X group is incorporated in theorientation as listed;

wherein R^(A) and R^(B) are each independently selected from the groupconsisting of hydrogen, fluoro, C₁₋₆alkyl, fluorinated C₁₋₂alkyl,C₃₋₆cycloalkyl, phenyl, benzyl, phenyl-ethyl- and —C(O)—OC₁₋₂alkyl;provided that when one of R^(A) or R^(B) is C₃₋₆cycloalkyl, phenyl,benzyl, phenyl-ethyl- or —C(O)O—C₁₋₂alkyl, then the other of R^(A) orR^(B) is hydrogen;

alternatively, when X is selected from the group consisting of—CR^(A)R^(B)—, —CR^(A)R^(B)—CH₂— and —CR^(A)R^(B)—CR^(C)═, R^(A) andR^(B) may be taken together with the carbon atom to which they are boundto form C₃₋₆cycloalkyl;

R^(C) is selected from the group consisting of hydrogen and C₁₋₃alkyl;

R^(D) is selected from the group consisting of hydrogen and C₁₋₃alkyl;

is selected from the group consisting of C₅₋₆cycloalkyl,C₅₋₆cycloalkenyl, phenyl, four to six membered monocyclic heterocyclyland nine to ten membered bicyclic heterocyclyl;

wherein the phenyl, four to six membered monocyclic heterocyclyl or nineto ten membered bicyclic heterocyclyl is optionally substituted with oneor more substituents independently selected from the group consisting ofhalogen, oxo, C₁₋₄alkyl, fluorinated C₁₋₂alkyl, —NR^(D)R^(E), cyano,imino, cyanoimino, —S—(C₁₋₄alkyl), —SO—(C₁₋₄alkyl), —SO₂—(C₁₋₄alkyl),—C(O)OH, —C(O)O—(C₁₋₃alkyl) and —C(O)—NR^(D)R^(E);

wherein R^(D) and R^(E) are each independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

and tautomers and pharmaceutically acceptable salts thereof.

The present invention is further directed to compounds of formula (II)

wherein

is selected from the group consisting of naphth-2-yl, indol-5-yl,indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl,benzothiazol-5-yl, benzothiazol-6-yl, benzoisothiazol-6-yl,chroman-7-yl, chromen-7-yl, benzo[d][1,3]dioxol-5-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl and2,3-dihydro-benzo[b][1,4]dioxin-6-yl;

wherein the naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl,benzimidazol-5-yl, benzimidazol-6-yl, benzothiazol-5-yl,benzothiazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl,benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl; is optionally substituted on thephenyl portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, cyano, C₁₋₃alkyl, fluorinatedC₁₋₂alkyl, C₁₋₃alkoxy, fluorinated C₁₋₂alkoxy and C₃₋₆cycloalkyl;

and wherein the naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl,benzimidazol-5-yl, benzimidazol-6-yl, benzothiazol-5-yl,benzothiazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl,benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl; is further optionally substitutedon the

portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, cyano, C₁₋₃alkyl, fluorinatedC₁₋₂alkyl, C₁₋₃alkoxy, fluorinated C₁₋₂alkoxy and C₃₋₆cycloalkyl;

R³ is selected from the group consisting of hydrogen, halogen andC₁₋₄alkyl;

R⁴ is selected from the group consisting of hydrogen, halogen andC₁₋₄alkyl;

R⁵ is selected from the group consisting of hydrogen, fluoro, hydroxy,C₁₋₄alkyl, C₃₋₆cycloalkyl and —C(O)NR^(U)R^(V); wherein R^(U) and R^(V)are each independently selected from the group consisting of hydrogenand C₁₋₂alkyl;

is a ring structure selected from the group consisting of cyclopentyl,cyclohexyl, azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl,piperidin-4-yl, morpholin-2-yl, thiomorpholin-4-yl,tetrahydropyran-4-yl, 4,5,6,7-tetrahydro-2H-indazol-5-yl,1,5-dihydro-imidazol-5-yl, 3,5-dihydro-imidazol-5-yl,4,5-dihydro-imidazol-4-yl, 4,5-dihydro-imidazol-5-yl, imidazolidin-4-yl,imidazolidin-5-yl, 4,5-dihydro-pyrrol-3-yl, 4,5-dihydro-pyrazol-5-yl,1,2,5-thiadiazolidin-3-yl, 4,5,6,7-tetrahydro-benzo[d]isoxazol-5-yl,imidazo[1,2-a]imdazol-3-yl, imidazo[2,1-c][1,2,4]triazol-5-yl,6,7-dihydro-5H-imidazo[2,1-c][1,2,4]triazol-6-yl,tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-6-yl,6-oxabicyclo[3.2.1]octan-5-yl, 8-azabicyclo[3.2.1]octan-3-yl,6-azabicyclo[3.2.1]octan-4-yl, 1-oxa-3-azaspiro[4.5]decan-7-yl,2-azaspiro[4.5]decan-8-yl, 1λ²,3-diazaspiro[4.5]decan-7-yl,2-azaspiro[5.5]undecan-9-yl, 3-azaspiro[5.5]undecan-9-yl,1,3-diazaspiro[4.5]decan-8-yl and octahydro-cyclopenta[c]pyrrol-5-yl;

wherein the

ring structure is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₄alkyl, hydroxy,oxo, thioxo, cyano, —NR^(F)R^(G), —NH(CN), ═NH, ═N(CN), ═N(OH),═N(O—C₁₋₂alkyl), —CH₂—NR^(F)R^(G)—C(O)—NR^(F)R^(G), —OC(O)—NR^(F)R^(G),—C(O)—CH₂OH, —SO₂—(C₁₋₄alkyl), —NR^(F)—SO₂—(C₁₋₄alkyl) and—C(NR^(F)R^(G))(═N—CN);

wherein R^(F) and R^(G) are each independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

provided that when R³ is hydrogen, R⁴ is hydrogen, R⁵ is selected fromthe group consisting of hydrogen, C₁₋₄alkyl and C₃₋₆cycloalkyl, and

is selected from the group consisting of pyrrolidin-3-yl-2-one andpiperidin-3-yl-2-one, then

is other than indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-ylor benzimidazol-6-yl; wherein the indol-5-yl, indazol-5-yl,indazol-6-yl, benzimidazol-5-yl or benzimidazol-6-yl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁₋₃alkyl and C₃₋₆cycloalkyl;

provided further that when

is selected from the group consisting of indol-5-yl, indazol-6-yl andbenzimidazol-6-yl; wherein the indol-5-yl, indazol-6-yl orbenzimidazol-6-yl is optionally substituted with one to two substituentsindependently selected from the group consisting of halogen andC₁₋₃alkyl, R³ is hydrogen, R⁴ is hydrogen and R⁵ is methyl, then

is other than pyrrolidin-3-yl-2-one or piperidin-3-yl-2-one;

provided further than when

is selected from the group consisting of naphth-2-yl and8-fluoro-naphth-2-yl, R³ is selected from the group consisting ofhydrogen, halogen and C₁₋₃alkyl, R⁴ is hydrogen and R⁵ is selected fromthe group consisting of hydrogen, C₁₋₄alkyl and C₃₋₆cycloalkyl, then

is other than imidazolidin-4-yl-2-one;

and tautomers and pharmaceutically acceptable salts thereof.

The present invention is directed to compounds of formula (III)

wherein

is selected from the group consisting of naphth-2-yl, indol-5-yl,indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl,benzothiazol-5-yl, benzothiazol-6-yl, benzoisothiazol-6-yl,chroman-7-yl, chromen-7-yl, benzo[d][1,3]dioxol-5-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl and2,3-dihydro-benzo[b][1,4]dioxin-6-yl;

wherein the naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl,benzimidazol-5-yl, benzimidazol-6-yl, benzothiazol-5-yl,benzothiazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl,benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl is optionally substituted on thephenyl portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, cyano, C₁₋₃alkyl, fluorinatedC₁₋₂alkyl, C₁₋₃alkoxy, fluorinated C₁₋₂alkoxy and C₃₋₆cycloalkyl;

and wherein the naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl,benzimidazol-5-yl, benzimidazol-6-yl, benzothiazol-5-yl,benzothiazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl,benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl; is further optionally substitutedon the

portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, cyano, C₁₋₃alkyl, fluorinatedC₁₋₂alkyl, C₁₋₃alkoxy, fluorinated C₁₋₂alkoxy and C₃₋₆cycloalkyl;

R⁶ is selected from the group consisting of hydrogen, halogen andC₁₋₄alkyl;

R⁷ is selected from the group consisting of hydrogen, halogen andC₁₋₄alkyl;

Y is selected from the group consisting of —CR^(H)R^(J)— and—CR^(H)R^(J)—CHR^(K)—;

wherein R^(H) and R^(J) are each independently selected from the groupconsisting of hydrogen, halogen, hydroxy, C₁₋₄alkyl, fluorinatedC₁₋₂alkyl, C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, phenyl, benzyl andphenyl-ethyl-; provided that when one of R^(H) or R^(J) isC₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, phenyl, benzyl or phenylethyl-, thenthe other of R^(H) or R^(J) is hydrogen; and wherein R^(K) is selectedfrom the group consisting of hydrogen and C₁₋₄alkyl;

alternatively, when Y is —CR^(H)R^(J)—, then R^(H) and R^(J) may betaken together with the carbon atom to which they are bound to formC₃₋₆cycloalkyl;

Z is selected from the group consisting of —C(O)—NR^(L)R^(M),—C(O)—NH—OR^(N), —C(O)—NH—SO₂—R^(N); —C(O)—NH(CH(CH₂OH)₂),—C(O)—NH(C(CH₂OH)₃), —C(O)—NH—(CH₂CH₂O)_(a)—R^(N),—C(O)—NH—CH(CH₂O—(CH₂CH₂O)_(b)—R^(N))₂,—C(O)—NH—C(CH₂O—(CH₂CH₂O)_(b)—R^(N))₃), —C(O)—NH—CH₂CH₂—NR^(P)R^(Q),—C(O)—NH—(CH₂CH₂O)_(a)—CH₂CH₂—NR^(P)R^(Q), —NR^(S)—C(O)—NR^(P)R^(Q),—NR^(S)—C(O)—NH—CH₂CH₂—NR^(P)R^(Q) and —NR^(S)—C(NH₂)═N—CN;

wherein a is an integer from 1 to 6;

wherein b is an integer from 0 to 3;

wherein R^(L) and R^(M) are each independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

wherein R^(N) is selected from the group consisting of hydrogen andC₁₋₂alkyl;

wherein R^(P) and R^(Q) are each independently selected from the groupconsisting of hydrogen and C₁₋₂alkyl;

and wherein R^(S) is selected from the group consisting of hydrogen andC₁₋₂alkyl;

and tautomers and pharmaceutically acceptable salts thereof.

The present invention is further directed to processes for thepreparation of the compounds of formula (I), compounds of formula (II)and compounds of formula (III). The present invention is furtherdirected to a product prepared according to the process describedherein.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and the product prepared accordingto the process described herein. An illustration of the invention is apharmaceutical composition made by mixing the product prepared accordingto the process described herein and a pharmaceutically acceptablecarrier. Illustrating the invention is a process for making apharmaceutical composition comprising mixing the product preparedaccording to the process described herein and a pharmaceuticallyacceptable carrier.

Exemplifying the invention are methods of treating a disorder mediatedby the EP3 receptor (selected from the group consisting Type I diabetesmellitus, impaired glucose tolerance (IGT), impaired fasting glucose(IFG), gestational diabetes, Type II diabetes mellitus, Syndrome X (alsoknown as Metabolic Syndrome), obesity, nephropathy, neuropathy,retinopathy, restenosis, thrombosis, coronary artery disease,hypertension, angina, atherosclerosis, heart disease, heart attack,ischemia, stroke, nerve damage or poor blood flow in the feet,neurodegenerative disorders (such as Alzheimer's disease, intracerebralhemorrhage, and the like), non-alcoholic steatohepatitis (NASH),non-alcoholic fatty liver disease (NAFLD), liver fibrosis, cataracts,polycystic ovarian syndrome, premature labor, irritable bowel syndrome,bladder over-activity, inflammation, pain (for example, arthritic pain,neuropathic pain, and the like) and cancer (for example, prostatecancer, pancreatic cancer, colon cancer, liver cancer, thyroid cancer,breast cancer, and the like)) comprising administering to a subject inneed thereof a therapeutically effective amount of any of the compoundsor pharmaceutical compositions described above.

In an embodiment, the present invention is directed to a compound offormula (I) or compound of formula (II) or compound of formula (III) foruse as a medicament. In another embodiment, the present invention isdirected to a compound of formula (I) or compound of formula (II) orcompound of formula (III) for use in the treatment of a disordermediated by the EP3 receptor (selected from the group consisting of TypeI diabetes mellitus, impaired glucose tolerance (IGT), impaired fastingglucose (IFG), gestational diabetes, Type II diabetes mellitus, SyndromeX (also known as Metabolic Syndrome), obesity, nephropathy, neuropathy,retinopathy, restenosis, thrombosis, coronary artery disease,hypertension, angina, atherosclerosis, heart disease, heart attack,ischemia, stroke, nerve damage or poor blood flow in the feet,neurodegenerative disorders (such as Alzheimer's disease, intracerebralhemorrhage, and the like), non-alcoholic steatohepatitis (NASH),non-alcoholic fatty liver disease (NAFLD), liver fibrosis, cataracts,polycystic ovarian syndrome, premature labor, irritable bowel syndrome,bladder over-activity, inflammation, pain (for example, arthritic pain,neuropathic pain, and the like) and cancer (for example, prostatecancer, pancreatic cancer, colon cancer, liver cancer, thyroid cancer,breast cancer, and the like)).

In another embodiment, the present invention is directed to acomposition comprising a compound of formula (I) or compound of formula(II) or compound of formula (III) for the treatment of a disordermediated by the EP3 receptor (selected from the group consisting of TypeI diabetes mellitus, impaired glucose tolerance (IGT), impaired fastingglucose (IFG), gestational diabetes, Type II diabetes mellitus, SyndromeX (also known as Metabolic Syndrome), obesity, nephropathy, neuropathy,retinopathy, restenosis, thrombosis, coronary artery disease,hypertension, angina, atherosclerosis, heart disease, heart attack,ischemia, stroke, nerve damage or poor blood flow in the feet,neurodegenerative disorders (such as Alzheimer's disease, intracerebralhemorrhage, and the like), non-alcoholic steatohepatitis (NASH),non-alcoholic fatty liver disease (NAFLD), liver fibrosis, cataracts,polycystic ovarian syndrome, premature labor, irritable bowel syndrome,bladder over-activity, inflammation, pain (for example, arthritic pain,neuropathic pain, and the like) and cancer (for example, prostatecancer, pancreatic cancer, colon cancer, liver cancer, thyroid cancer,breast cancer, and the like)).

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)Type I diabetes mellitus, (b) impaired glucose tolerance (IGT), (c)impaired fasting glucose (IFG), (d) gestational diabetes, (e) Type IIdiabetes mellitus, (f) Syndrome X (also known as Metabolic Syndrome),(g) obesity, (h) nephropathy, (i) neuropathy, (j) retinopathy, (k)restenosis, (I) thrombosis, (m) coronary artery disease, (n)hypertension, (o) angina, (p) atherosclerosis, (q) heart disease, (r)heart attack, (s) ischemia, (t) stroke, (u) nerve damage or poor bloodflow in the feet, (v) neurodegenerative disorders (such as Alzheimer'sdisease, intracerebral hemorrhage, and the like), (w) non-alcoholicsteatohepatitis (NASH), (x) non-alcoholic fatty liver disease (NAFLD),(y) liver fibrosis, (z) cataracts, (aa) polycystic ovarian syndrome,(ab) premature labor, (ac) irritable bowel syndrome, (ad) bladderover-activity, (ae) inflammation, (af) pain (for example, arthriticpain, neuropathic pain, and the like) and (ag) cancer (for example,prostate cancer, pancreatic cancer, colon cancer, liver cancer, thyroidcancer, breast cancer, and the like), in a subject in need thereof.

In another example, the present invention is directed to a compound asdescribed herein for use in a methods for treating a disorder selectedfrom the group consisting of Type I diabetes mellitus, impaired glucosetolerance (IGT), impaired fasting glucose (IFG), gestational diabetes,Type II diabetes mellitus, Syndrome X (also known as MetabolicSyndrome), obesity, nephropathy, neuropathy, retinopathy, restenosis,thrombosis, coronary artery disease, hypertension, angina,atherosclerosis, heart disease, heart attack, ischemia, stroke, nervedamage or poor blood flow in the feet, neurodegenerative disorders (suchas Alzheimer's disease, intracerebral hemorrhage, and the like),non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease(NAFLD), liver fibrosis, cataracts, polycystic ovarian syndrome,premature labor, irritable bowel syndrome, bladder over-activity,inflammation, pain (for example, arthritic pain, neuropathic pain, andthe like) and cancer (for example, prostate cancer, pancreatic cancer,colon cancer, liver cancer, thyroid cancer, breast cancer, and thelike), in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein

R¹, R², X and

are as herein defined.

The present invention is further directed to compounds of formula (II)

wherein

R³, R⁴, R⁵ and

are as herein defined.

The present invention is further directed to compounds of formula (III)

wherein

R⁶, R⁷, Y and Z are as herein defined.

The compounds of formula (I), compounds of formula (II) and compounds offormula (III) of the present invention are antagonists of the EP3receptor, useful in the treatment of disorders and conditions thatrespond to antagonism of the EP3 receptor, including, but not limitedto: Type I diabetes mellitus, impaired glucose tolerance (IGT), impairedfasting glucose (IFG), gestational diabetes, Type II diabetes mellitus,Syndrome X (also known as Metabolic Syndrome), obesity, nephropathy,neuropathy, retinopathy, restenosis, thrombosis, coronary arterydisease, hypertension, angina, atherosclerosis, heart disease, heartattack, ischemia, stroke, nerve damage or poor blood flow in the feet,neurodegenerative disorders (such as Alzheimer's disease, intracerebralhemorrhage, and the like), non-alcoholic steatohepatitis (NASH),non-alcoholic fatty liver disease (NAFLD), liver fibrosis, cataracts,polycystic ovarian syndrome, premature labor, irritable bowel syndrome,bladder over-activity, inflammation, pain (for example, arthritic pain,neuropathic pain, and the like) and cancer (for example, prostatecancer, pancreatic cancer, colon cancer, liver cancer, thyroid cancer,breast cancer, and the like).

In an embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of naphth-2-yl, indol-5-yl,indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl,benzothiazol-5-yl, benzothiazol-6-yl, benzoisothiazol-6-yl,chroman-7-yl, chromen-7-yl, benzo[d][1,3]dioxol-5-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, and2,3-dihydro-benzo[b][1,4]dioxin-6-yl; wherein the naphth-2-yl,indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl,benzimidazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl,benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl,benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl; is optionally substituted on thephenyl portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, cyano, C₁₋₃alkyl, fluorinatedC₁₋₂alkyl, C₁₋₃alkoxy, fluorinated C₁₋₂alkoxy and C₃₋₆cycloalkyl; andwherein the naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl,benzimidazol-5-yl, benzimidazol-6-yl, benzothiazol-5-yl,benzothiazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl,benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl is further optionally substitutedon the

portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, cyano, C₁₋₃alkyl, fluorinatedC₁₋₂alkyl, C₁₋₃alkoxy, fluorinated C₁₋₂alkoxy and C₃₋₆cycloalkyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of naphth-2-yl, indol-5-yl,indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl,benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl,benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl and2,3-dihydro-benzo[b][1,4]dioxin-6-yl; wherein the naphth-2-yl,indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl,benzimidazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl,benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl; is optionally substituted on thephenyl portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, cyano, C₁₋₃alkyl, fluorinatedC₁₋₂alkyl and C₃₋₆cycloalkyl; and wherein the naphth-2-yl, indol-5-yl,indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl,benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl,benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, or2,3-dihydro-benzo[b][1,4]dioxin-6-yl is further optionally substitutedon the

portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, cyano, C₁₋₃alkyl, fluorinatedC₁₋₂alkyl and C₃₋₆cycloalkyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of naphth-2-yl,8-fluoro-naphth-2-yl, 5,7-difluoro-naphth-2-yl,6,8-difluoro-naphth-2-yl, 8-ethyl-naphth-2-yl, 8-isopropyl-naphth-2-yl,8-trifluoromethyl-naphth-2-yl, 8-cyano-naphth-2-yl,2,2-dimethyl-chroman-7-yl, 2,2-dimethyl-chromen-7-yl,1-methyl-indol-5-yl, 2-ethyl-indazol-6-yl,1-ethyl-4-chloro-indazol-6-yl, 1-ethyl-4-fluoro-indazol-6-yl,2-ethyl-4-fluoro-indazol-5-yl, 2-ethyl-4-methyl-indazol-6-yl,1-ethyl-3-methyl-indazol-6-yl, 1-ethyl-4-methyl-indazol-6-yl,1-ethyl-5-methyl-indazol-6-yl, 1-ethyl-5-fluoro-indazol-6-yl,2-ethyl-4-methyl-indazol-6-yl, 1-isopropyl-4-fluoro-indazol-6-yl,1-cyclopentyl-4-fluoro-indazol-6-yl,1-methyl-7-chloro-benzimidazol-5-yl, 1-ethyl-7-fluoro-benzimidazol-6-yl,benzoisothiazol-6-yl, 4-methyl-3,4-dihydro-benzo[b][1,4]oxazin-6-yl,4-ethyl-3,4-dihydro-benzo[b][1,4]oxazin-6-yl,4-ethyl-8-fluoro-3,4-dihydro-benzo[b][1,4]oxazin-6-yl,4-ethyl-3,4-dihydro-benzo[b][1,4]oxazin-6-yl-3-one,2,3-dihydro-benzo[b][1,4]dioxin-6-yl and2,2-difluoro-benzo[d][1,3]dioxol-5-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of naphth-2-yl,8-fluoro-naphth-2-yl, 5,7-difluoro-naphth-2-yl,6,8-difluoro-naphth-2-yl, 8-ethyl-naphth-2-yl, 8-isopropyl-naphth-2-yl,8-trifluoromethyl-naphth-2-yl, 8-cyano-naphth-2-yl, 1-methyl-indol-5-yl,1-ethyl-4-chloro-indazol-6-yl, 1-ethyl-4-fluoro-indazol-6-yl,1-ethyl-5-fluoro-indazol-6-yl, 1-ethyl-4-methyl-indazol-6-yl,2-ethyl-4-methyl-indazol-6-yl, 1-isopropyl-4-fluoro-indazol-6-yl,1-cyclopentyl-4-fluoro-indazol-6-yl,1-methyl-7-chloro-benzimidazol-5-yl,4-methyl-3,4-dihydro-benzo[b][1,4]oxazin-6-yl,4-ethyl-3,4-dihydro-benzo[b][1,4]oxazin-6-yl,4-ethyl-8-fluoro-3,4-dihydro-benzo[b][1,4]oxazin-6-yl,4-ethyl-3,4-dihydro-benzo[b][1,4]oxazin-6-yl-3-one and2,3-dihydro-benzo[b][1,4]dioxin-6-yl.

In another embodiment, the present invention is directed to compounds offormula (III) wherein

is selected from the group consisting of naphth-2-yl,8-fluoro-naphth-2-yl, 5,7-difluoro-naphth-2-yl, 8-ethyl-naphth-2-yl,1-methyl-indol-5-yl, 1-ethyl-4-chloro-indazol-6-yl,1-ethyl-4-fluoro-indazol-6-yl, 1-isopropyl-4-fluoro-indazol-6-yl,4-ethyl-8-fluoro-3,4-dihydro-benzo[b][1,4]oxazin-6-yl and2,3-dihydro-benzo[b][1,4]dioxin-6-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of 8-fluoro-naphth-2-yl,8-ethyl-naphth-2-yl, 1-ethyl-4-chloro-indazol-6-yl,1-ethyl-4-fluoro-indazol-6-yl and4-ethyl-8-fluoro-3,4-dihydro-benzo[b][1,4]oxazin-6-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of 8-fluoro-naphth-2-yl,1-ethyl-4-chloro-indazol-6-yl, 1-ethyl-4-fluoro-indazol-6-yl and4-ethyl-8-fluoro-3,4-dihydro-benzo[b][1,4]oxazin-6-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of 8-fluoro-naphth-2-yl and1-ethyl-4-fluoro-indazol-6-yl.

In an embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting ofhydrogen, halogen and C₁₋₂alkyl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R¹ is selectedfrom the group consisting of hydrogen, fluoro, chloro, bromo and methyl.In another embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting ofhydrogen, fluoro and methyl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R¹ ishydrogen.

In an embodiment, the present invention is directed to compounds offormula (I) wherein R² is selected from the group consisting ofhydrogen, halogen and C₁₋₂alkyl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R² is selectedfrom the group consisting of hydrogen, chloro, bromo and methyl. Inanother embodiment, the present invention is directed to compounds offormula (I) wherein R² is selected from the group consisting ofhydrogen, fluoro and methyl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R² ishydrogen.

In an embodiment, the present invention is directed to compounds offormula (I) wherein —X

is selected from the group consisting of —CR^(A)R^(B)—,—CR^(A)R^(B)—CH₂—, —CH₂—CHR^(C)—, —CR^(A)R^(B)—CR^(C)═, —C(R^(A))═,—CR^(A)R^(B)—N(R^(D))—, —CR^(A)R^(B)—CH₂—N(R^(D))—,—CR^(A)R^(B)—C(O)—N(R^(D))—, —CR^(A)R^(B)—CH₂—C(O)—N(R^(D))—,—CR^(A)R^(B)—C(O)—N(R^(D))—SO₂—, —CR^(A)R^(B)—CH₂—C(O)—N(R^(D))—SO₂—,—CR^(A)R^(B)—N(R^(D))—SO₂—, —CR^(A)R^(B)—CH₂—N(R^(D))—SO₂; and—CR^(A)R^(B)—CH₂—SO₂—; wherein the X group is incorporated in theorientation as listed; wherein R^(A) and R^(B) are each independentlyselected from the group consisting of hydrogen, fluoro, C₁₋₆alkyl,C₃₋₆cycloalkyl, phenyl, benzyl and —C(O)—OC₁₋₂alkyl; provided that whenone of R^(A) or R^(B) is C₃₋₆cycloalkyl, phenyl, benzyl, or—C(O)O—C₁₋₂alkyl, then the other of R^(A) or R^(B) is hydrogen;alternatively, when X is selected from the group consisting of—CR^(A)R^(B)—CH₂— and —CR^(A)R^(B)—CR^(C)═, R^(A) and R^(B) may be takentogether with the carbon atom to which they are bound to formC₃₋₆cycloalkyl; wherein R^(C) is selected from the group consisting ofhydrogen and C₁₋₃alkyl; and wherein R^(D) is selected from the groupconsisting of hydrogen and C₁₋₃alkyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein —X—

is selected from the group consisting of —CR^(A)R^(B)—,—CR^(A)R^(B)—CH₂—, —CH₂—CHR^(C)—, —CR^(A)R^(B)—CR^(C)═, —C(R^(A))═,—CR^(A)R^(B)—N(R^(D))—, —CR^(A)R^(B)—C(O)—N(R^(D))—,—CR^(A)R^(B)—CH₂—C(O)—N(R^(D))—, —CR^(A)R^(B)—C(O)—N(R^(D))—SO₂—,—CR^(A)R^(B)—CH₂—C(O)—N(R^(D))—SO₂—, —CR^(A)R^(B)—N(R^(D))—SO₂— and—CR^(A)R^(B)—CH₂—SO₂—; wherein the X group is incorporated in theorientation as listed; wherein R^(A) and R^(B) are each independentlyselected from the group consisting of hydrogen, fluoro, C₁₋₆alkyl,C₃₋₆cycloalkyl, phenyl, benzyl and —C(O)O—(C₁₋₂alkyl); provided thatwhen one of R^(A) or R^(B) is C₃₋₆cycloalkyl, phenyl, benzyl or—C(O)O—C₁₋₂alkyl, then the other of R^(A) or R^(B) is hydrogen;alternatively, when X is selected from the group consisting of—CR^(A)R^(B)—CH₂— and —CR^(A)R^(B)—CR^(C)═, R^(A) and R^(B) may be takentogether with the carbon atom to which they are bound to formC₃₋₅cycloalkyl; wherein R^(C) is selected from the group consisting ofhydrogen and C₁₋₄alkyl; and wherein R^(D) is hydrogen.

In an embodiment, the present invention is directed to compounds offormula (I) wherein R^(A) and R^(B) are each independently selected fromthe group consisting of hydrogen, fluoro, C₁₋₆alkyl, C₃₋₆cycloalkyl,phenyl, benzyl and —C(O)—OC₁₋₂alkyl; provided that when one of R^(A) orR^(B) is C₃₋₆cycloalkyl, phenyl, benzyl, or —C(O)O—C₁₋₂alkyl, then theother of R^(A) or R^(B) is hydrogen.

In another embodiment, the present invention is directed to compounds offormula (I) wherein X is selected from the group consisting of—CR^(A)R^(B)—CH₂— and —CR^(A)R^(B)—CR^(C)═, and R^(A) and R^(B) aretaken together with the carbon atom to which they are bound to formC₃₋₆cycloalkyl. In another embodiment, the present invention is directedto compounds of formula (I) wherein X is selected from the groupconsisting of —CR^(A)R^(B)—CH₂— and —CR^(A)R^(B)—CR^(C)═, and R^(A) andR^(B) are taken together with the carbon atom to which they are bound toform C₃₋₅cycloalkyl.

In an embodiment, the present invention is directed to compounds offormula (I) wherein X is —CR^(A)R^(B), and R^(A) and R^(B) are takentogether with the carbon atom to which they are bound to formC₃₋₆cycloalkyl. In another embodiment, the present invention is directedto compounds of formula (I) wherein X is —CR^(A)R^(B)—CH₂—, and R^(A)and R^(B) are taken together with the carbon atom to which they arebound to form C₃₋₆cycloalkyl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein X is—CR^(A)R^(B)—CR^(C)═, and R^(A) and R^(B) are taken together with thecarbon atom to which they are bound to form C₃₋₆cycloalkyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein —X

is selected from the group consisting of —CH₂—, —C(ethyl)₂-,—CH(isopropyl)-, -(syn)-CH(isopropyl)-, -(anti)-CH(isopropyl)-,-(syn)-CH(S-isopropyl)-CH₂—, -(anti)-CH(S-isopropyl)-CH₂—,—CH(C(O)O-ethyl)-, —C(methyl)₂-CH₂—, —C(ethyl)₂-CH₂—,—CH(isopropyl)-CH₂—, —CH₂—CH(isopropyl)-, -(syn)-CH(isopropyl)-CH₂—,-(anti)-CH(isopropyl)-CH₂—, —C(methyl)₂-CH═, —C(methyl)₂-(Z)—CH═,—C(methyl)₂-(E)-CH═, —C(ethyl)₂-CH═, —C(ethyl)₂-(E)-CH═,—C(ethyl)₂-(Z)—CH═, —CH(isopropyl)-CH═, —CH(isopropyl)-(E)-CH═,—CH(isopropyl)-(Z)—CH═, —CH(R*-isopropyl)-(Z)—CH═,—CH(S*-isopropyl)-(Z)—CH═, —CH(isopropyl)-C(methyl)=,—CH(isopropyl)-(E)-C(methyl)=, —CH(isopropyl)-(Z)—C(methyl)=,—CH(t-butyl)-CH═, —CH(t-butyl)-(Z)—CH═, —CH(t-butyl)-(E)-CH═,—CH(n-pent-3-yl)-CH═, —CH(n-pent-3-yl)-(Z)—CH═,—CH(n-pent-3-yl)-(E)-CH═, —CH(cyclopropyl)-CH═,—CH(cyclopropyl)-(Z)—CH═, —CH(cyclopropyl)-(E)-CH═,—CH(cyclopentyl)-CH═, —CH(cyclopentyl)-(Z)—CH═,—CH(cyclopentyl)-(E)-CH═, —CH(cyclohexyl)-CH═, —CH(cyclohexyl)-(Z)—CH═,—CH(cyclohexyl)-(E)-CH═, —CH(phenyl)-CH═, —CH(phenyl)-(E)-CH═,—CH(phenyl)-(Z)—CH═, —CH(benzyl)-CH═, —CH(benzyl)-(E)-CH═,—CH(benzyl)-(Z)—CH═, —CH₂—C(isopropyl)=, —CH₂-(E)-C(isopropyl)=,—CH₂—(Z)—C(isopropyl)=, —CH(C(O)O-ethyl)=, —C(isopropyl)=,—(Z)—C(isopropyl)=, -(E)-C(isopropyl)=, -cyclopropyl-1,1-yl-CH═,-cyclopropyl-1,1-yl-(E)-CH═, -cyclopropyl-1,1-yl-(Z)—CH═,-cyclopent-1,1-yl-CH₂—, -cyclopent-1,1-yl-CH═,-cyclopent-1,1-yl-(E)-CH═, -cyclopent-1,1-yl-(Z)—CH═,—CH(isopropyl)-CH₂—SO₂—, —CH(isopropyl)-NH—, —CH(isopropyl)-C(O)—NH—,—CH(isopropyl)-CH₂—C(O)—NH—, —CH(isopropyl)-C(O)—NH—SO₂—,—CF(isopropyl)-C(O)—NH—SO₂—, —CH(isopropyl)-CH₂—C(O)—NH—SO₂, and—CH(isopropyl)-NH—SO₂—; wherein the X group is incorporated in theorientation as listed.

In another embodiment, the present invention is directed to compounds offormula (I) wherein —X

is selected from the group consisting of —CH₂—, —C(ethyl)₂-,—CH(isopropyl)-, -(syn)-CH(isopropyl)-, -(anti)-CH(isopropyl)-,-(syn)-CH(S-isopropyl)-CH₂—, -(anti)-CH(S-isopropyl)-CH₂—,—CH(C(O)O-ethyl)-, —C(methyl)₂—CH₂—, —C(ethyl)₂-CH₂—,—CH(isopropyl)-CH₂—, —CH₂—CH(isopropyl)-, -(syn)-CH(isopropyl)-CH₂—,-(anti)-CH(isopropyl)-CH₂—, —C(methyl)₂-CH═, —C(methyl)₂-(Z)—CH═,—C(methyl)₂-(E)-CH═, —C(ethyl)₂-CH═, —C(ethyl)₂-(E)-CH═,—C(ethyl)₂-(Z)—CH═, —CH(isopropyl)-CH═, —CH(isopropyl)-(E)-CH═,—CH(isopropyl)-(Z)—CH═, —CH(R*-isopropyl)-(Z)—CH═,—CH(S*-isopropyl)-(Z)—CH═, —CH(isopropyl)-(E)-C(methyl)=,—CH(isopropyl)-(Z)—C(methyl)=, —CH(t-butyl)-(E)-CH═,—CH(n-pent-3-yl)-(E)-CH═, —CH(cyclopropyl)-(Z)—CH═,—CH(cyclopentyl)-(Z)—CH═, —CH(cyclopentyl)-(E)-CH═,—CH(cyclohexyl)-(Z)—CH═, —CH(cyclohexyl)-(E)-CH═, —CH(phenyl)-(Z)—CH═,—CH(benzyl)-(E)-CH═, —CH₂-(E)-C(isopropyl)=, —CH(C(O)O-ethyl)=,—(Z)—C(isopropyl)=, -(E)-C(isopropyl)=, -cyclopropyl-1,1-yl-(E)-CH═,-cyclopent-1,1-yl-CH₂—, -cyclopent-1,1-yl-(E)-CH═,—CH(isopropyl)-CH₂—SO₂—, —CH(isopropyl)-NH—, —CH(isopropyl)-C(O)—NH—,—CH(isopropyl)-CH₂—C(O)—NH—, —CH(isopropyl)-C(O)—NH—SO₂—,—CF(isopropyl)-C(O)—NH—SO₂—, —CH(isopropyl)-CH₂—C(O)—NH—SO₂, and—CH(isopropyl)-NH—SO₂—; wherein the X group is incorporated in theorientation as listed.

In another embodiment, the present invention is directed to compounds offormula (I) wherein —X

is selected from the group consisting of —CH₂—, —C(ethyl)₂-,—CH(isopropyl)-, -(syn)-CH(isopropyl)-, -(anti)-CH(isopropyl)-,—CH(C(O)O-ethyl)-, —C(methyl)₂-CH₂—, —C(ethyl)₂-CH₂—,—CH(isopropyl)-CH₂—, -(syn)-CH(isopropyl)-CH₂—,-(anti)-CH(isopropyl)-CH₂—, -(syn)-CH(S-isopropyl)-CH₂—,-(anti)-CH(S-isopropyl)-CH₂—, —CH₂—CH(isopropyl)-, —C(methyl)₂-(Z)—CH═,—C(ethyl)₂-(E)-CH═, —C(ethyl)₂-(Z)—CH═, —CH(isopropyl)-CH═,—CH(isopropyl)-(E)-CH═, —CH(isopropyl)-(Z)—CH═,—CH(R*-isopropyl)-(Z)—CH═, —CH(S*-isopropyl)-(Z)—CH═,—CH(isopropyl)-(E)-C(methyl)=, —CH(isopropyl)-(Z)—C(methyl)=,—CH(n-pent-3-yl)-(E)-CH═, —CH(cyclopropyl)-(Z)—CH═,—CH(cyclopentyl)-(E)-CH═, —CH(cyclopentyl)-(Z)—CH═,—CH(cyclohexyl)-(E)-CH═, —CH(cyclohexyl)-(Z)—CH═, —CH(phenyl)-(Z)—CH═,—CH(benzyl)-(E)-CH═, —CH₂-(E)-C(isopropyl)=, —CH(C(O)O-ethyl)=,—(Z)—C(isopropyl)=, -(E)-C(isopropyl)=, -cyclopropyl-1,1-yl-(E)-CH═,-cyclopent-1,1,-yl-CH₂—, -cyclopent-1,1,-yl-(E)-CH═,—CH(isopropyl)-CH₂—SO₂—, —CH(isopropyl)-NH—, —CH(isopropyl)-C(O)—NH—,—CH(isopropyl)-CH₂—C(O)—NH—, —CH(isopropyl)-C(O)—NH—SO₂—,—CF(isopropyl)-C(O)—NH—SO₂—, —CH(isopropyl)-CH₂—C(O)—NH—SO₂, and—CH(isopropyl)-NH—SO₂—; wherein the X group is incorporated in theorientation as listed.

In another embodiment, the present invention is directed to compounds offormula (I) wherein —X

is selected from the group consisting of —C(ethyl)₂-, —CH(isopropyl)-,-(anti)-CH(isopropyl)-, —C(methyl)₂-CH₂—, —C(ethyl)₂-CH₂—,—CH(isopropyl)-CH₂—, -(syn)-CH(isopropyl)-CH₂—,-(anti)-CH(isopropyl)-CH₂—, -(syn)-CH(S-isopropyl)-CH₂—,-(anti)-CH(S-isopropyl)-CH₂—, —CH₂—CH(isopropyl)-, —C(methyl)₂-(Z)—CH═,—C(ethyl)₂-(E)-CH═, —C(ethyl)₂-(Z)—CH═, —CH(isopropyl)-(E)-CH═,—CH(isopropyl)-(Z)—CH═, —CH(R*-isopropyl)-(Z)—CH═,—CH(S*-isopropyl)-(Z)—CH═, —CH(isopropyl)-(E)-C(methyl)=,—CH(isopropyl)-(Z)—C(methyl)=, —CH(n-pent-3-yl)-(E)-CH═,—CH(cyclopropyl)-(Z)—CH═, —CH(cyclopentyl)-(E)-CH═,—CH(cyclopentyl)-(Z)—CH═, —CH(cyclohexyl)-(E)-CH═,—CH(cyclohexyl)-(Z)—CH═, —CH(phenyl)-(Z)—CH═, —CH(benzyl)-(E)-CH═,—CH(C(O)O-ethyl)=, —(Z)—C(isopropyl)=, -(E)-C(isopropyl)=,-cyclopropyl-1,1-yl-(E)-CH═, -cyclopent-1,1,-yl-CH₂—,-cyclopent-1,1,-yl-(E)-CH═, —CH(isopropyl)-CH₂—SO₂—, —CH(isopropyl)-NH—,—CH(isopropyl)-C(O)—NH—, —CH(isopropyl)-CH₂—C(O)—NH—, and—CH(isopropyl)-NH—SO₂—; wherein the X group is incorporated in theorientation as listed.

In another embodiment, the present invention is directed to compounds offormula (I) wherein —X

is selected from the group consisting of —C(ethyl)₂-, —CH(isopropyl)-,—C(ethyl)₂-CH₂—, —CH(isopropyl)-CH₂—, -(syn)-CH(isopropyl)-CH₂—,-(anti)-CH(isopropyl)-CH₂—, -(syn)-CH(S-isopropyl)-CH₂—,-(anti)-CH(S-isopropyl)-CH₂—, —CH₂—CH(isopropyl)-, —C(ethyl)₂-(E)-CH═,—C(ethyl)₂-(Z)—CH═, —CH(isopropyl)-(E)-CH═, —CH(isopropyl)-(Z)—CH═,—CH(R*-isopropyl)-(Z)—CH═, —CH(S*-isopropyl)-(Z)—CH═,—CH(isopropyl)-(E)-C(methyl)=, —CH(isopropyl)-(Z)—C(methyl)=,—CH(cyclopropyl)-(Z)—CH═, —CH(cyclopentyl)-(E)-CH═,—CH(cyclopentyl)-(Z)—CH═, —CH(cyclohexyl)-(Z)—CH═, —CH(phenyl)-(Z)—CH═,—(Z)—C(isopropyl)=, -(E)-C(isopropyl)=, —CH(isopropyl)-NH— and—CH(isopropyl)-C(O)—NH—; wherein the X group is incorporated in theorientation as listed.

In another embodiment, the present invention is directed to compounds offormula (I) wherein —X

is selected from the group consisting of —C(ethyl)₂-, —CH(isopropyl)-,—C(ethyl)₂-CH₂—, —CH(isopropyl)-CH₂—, -(syn)-CH(isopropyl)-CH₂—,-(anti)-CH(isopropyl)-CH₂—, -(syn)-CH(S-isopropyl)-CH₂—,-(anti)-CH(S-isopropyl)-CH₂—, —C(ethyl)₂-(E)-CH═, —C(ethyl)₂-(Z)—CH═,—CH(isopropyl)-(E)-CH═, —CH(isopropyl)-(Z)—CH═,—CH(S*-isopropyl)-(Z)—CH═, —CH(isopropyl)-(E)-C(methyl)=,—CH(cyclopentyl)-(Z)—CH═, —CH(cyclohexyl)-(Z)═CH═, —CH(isopropyl)-NH—and —CH(isopropyl)-C(O)—NH—; wherein the X group is incorporated in theorientation as listed.

In another embodiment, the present invention is directed to compounds offormula (I) wherein —X

is selected from the group consisting of —C(ethyl)₂-, —C(ethyl)₂-CH₂—,—CH(isopropyl)-CH₂—, -(anti)-CH(isopropyl)-CH₂—, —C(ethyl)₂-(E)-CH═,—C(ethyl)₂-(Z)—CH═, —CH(isopropyl)-(E)-CH═, —CH(isopropyl)-(Z)—CH═, and—CH(isopropyl)-C(O)—NH—; wherein the X group is incorporated in theorientation as listed.

In an embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of C₅₋₆cycloalkyl,C₅₋₆cycloalkenyl, phenyl, four to six membered monocyclic heterocyclyland nine to ten membered bicyclic heterocyclyl; wherein the phenyl, fourto six membered monocyclic heterocyclyl or nine to ten membered bicyclicheterocyclyl is optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, oxo,C₁₋₄alkyl, fluorinated C₁₋₂alkyl, —NR^(D)R^(E), cyano, imino,cyanoimino, —SO₂—(C₁₋₂alkyl), —C(O)OH, —C(O)O—(C₁₋₃alkyl) and—C(O)—NR^(D)R^(E); wherein R^(D) and R^(E) are each independentlyselected from the group consisting of hydrogen and C₁₋₂alkyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of C₅₋₆cycloalkyl,C₅₋₆cycloalkenyl, phenyl, four to six membered monocyclic heterocyclyland nine to ten membered bicyclic heterocyclyl; wherein the phenyl, fourto six membered monocyclic heterocyclyl or nine to ten membered bicyclicheterocyclyl is optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, oxo,C₁₋₄alkyl, trifluoromethyl, —NR^(D)R^(E), imino, cyanoimino and—SO₂—(C₁₋₂alkyl); wherein R^(D) and R^(E) are each independentlyselected from the group consisting of hydrogen and C₁₋₂alkyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of cyclohexyl, cyclohex-1-en-1-yl,3,5-difluoro-phenyl, azetidin-3-yl, 1-methyl-azetidin-3-yl,pyrrolidin-3-yl, pyrrolidin-3-yl-2-one, R-pyrrolidin-3-yl-2-one,S-pyrrolidin-3-yl-2-one, 3-methyl-pyrrolidin-3-yl-2-one,piperidin-1-yl-2-one, piperidin-3-yl-2-one,1-(methylsulfonyl)-piperidin-4-yl, 4-(methylsulfonyl)-piperazin-1-yl,morpholin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl-1,1-dioxide,tetrahydropyran-4-yl, tetrahydro-thiopyran-4-yl,tetrahydro-thiopyran-4-yl-1,1-dioxide, 1,2-thiazinan-2-yl-1,1-dioxide,imidazol-2-yl, 5-methyl-imidazol-2-yl, 4,5-dimethyl-imidazol-2-yl,2-amino-imidazol-1-yl, imidazolidin-1-yl-2-one,imidazolidin-5-yl-2,4-dione, 1-methyl-imidazolidin-5-yl-2,4-dione,2-(cyanoimino)-imidazolidin-1-yl,5-isopropyl-imidazolidin-5-yl-2,4-dione, 1-methyl-benzimidazol-5-yl,1,5-dihydro-pyrrol-3-yl-2-one, 4,5-dichloro-thien-2-yl, pyridin-3-yl,oxazol-2-yl, oxazolidin-5-yl-2,4-dione,5-isopropyl-oxazolidin-5-yl-2,4-dione, thiazolidin-5-yl-2,4-dione,isoxazol-3-yl, 1,2,4-oxadiazol-3-yl-5-one, 1,3,4-oxadiazol-2-yl,5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl,5-isopropyl-1,3,4-oxadiazol-2-yl,5-trifluoromethyl-1,3,4-oxadiazol-2-yl, 5-amino-1,3,4-oxadiazol-2-yl,5-(dimethylamino)-1,3,4-oxadiazol-2-yl, thiazol-2-yl,2-amino-thiazol-5-yl, 2-imino-thiazol-3-yl,5-amino-1,3,4-thiadiazol-2-yl, 5-(dimethylamino)-1,3,4-thiadiazol-2-yl,1,3,4-triazol-2-yl, 1-methyl-1,3,4-triazol-5-yl,5-methyl-1,3,4-triazol-2-yl, 2-amino-1,3,4-triazol-1-yl,1-methyl-1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,3-amino-1,2,4-triazol-1-yl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yland 1,2,3,5-tetrazol-4-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of cyclohexyl, cyclohex-1-en-1-yl,3,5-difluoro-phenyl, azetidin-3-yl, 1-methyl-azetidin-3-yl,pyrrolidin-3-yl, pyrrolidin-3-yl-2-one, R-pyrrolidin-3-yl-2-one,S-pyrrolidin-3-yl-2-one, 3-methyl-pyrrolidin-3-yl-2-one,piperidin-1-yl-2-one, piperidin-3-yl-2-one,1-(methylsulfonyl)-piperidin-4-yl, 4-(methylsulfonyl)-piperazin-1-yl,morpholin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl-1,1-dioxide,tetrahydropyran-4-yl, tetrahydro-thiopyran-4-yl,tetrahydro-thiopyran-4-yl-1,1-dioxide, 1,2-thiazinan-2-yl-1,1-dioxide,imidazol-2-yl, 5-methyl-imidazol-2-yl, 4,5-dimethyl-imidazol-2-yl,2-amino-imidazol-1-yl, imidazolidin-1-yl-2-one,imidazolidin-5-yl-2,4-dione, 1-methyl-imidazolidin-5-yl-2,4-dione,2-(cyanoimino)-imidazolidin-1-yl,5-isopropyl-imidazolidin-5-yl-2,4-dione, 1-methyl-benzimidazol-5-yl,4,5-dichloro-thien-2-yl, pyridin-3-yl, oxazol-2-yl,oxazolidin-5-yl-2,4-dione, 5-isopropyl-oxazolidin-5-yl-2,4-dione,thiazolidin-5-yl-2,4-dione, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl-5-one,1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl,5-ethyl-1,3,4-oxadiazol-2-yl, 5-isopropyl-1,3,4-oxadiazol-2-yl,5-trifluoromethyl-1,3,4-oxadiazol-2-yl,5-(dimethylamino)-1,3,4-oxadiazol-2-yl, thiazol-2-yl,2-amino-thiazol-5-yl, 2-imino-thiazol-3-yl,5-amino-1,3,4-thiadiazol-2-yl, 5-(dimethylamino)-1,3,4-thiadiazol-2-yl,1,3,4-triazol-2-yl, 1-methyl-1,3,4-triazol-5-yl,5-methyl-1,3,4-triazol-2-yl, 2-amino-1,3,4-triazol-1-yl,1-methyl-1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,3-amino-1,2,4-triazol-1-yl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yland 1,2,3,5-tetrazol-4-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of cyclohexyl, azetidin-3-yl,1-methyl-azetidin-3-yl, pyrrolidin-3-yl, pyrrolidin-3-yl-2-one,R-pyrrolidin-3-yl-2-one, S-pyrrolidin-3-yl-2-one,3-methyl-pyrrolidin-3-yl-2-one, piperidin-1-yl-2-one,piperidin-3-yl-2-one, 1-(methylsulfonyl)-piperidin-4-yl,4-(methylsulfonyl)-piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl,thiomorpholin-4-yl-1,1-dioxide, tetrahydropyran-4-yl,tetrahydro-thiopyran-4-yl, tetrahydro-thiopyran-4-yl-1,1-dioxide,1,2-thiazinan-2-yl-1,1-dioxide, imidazol-2-yl, 5-methyl-imidazol-2-yl,4,5-dimethyl-imidazol-2-yl, 2-amino-imidazol-1-yl,imidazolidin-1-yl-2-one, imidazolidin-5-yl-2,4-dione,1-methyl-imidazolidin-5-yl-2,4-dione, 2-(cyanoimino)-imidazolidin-1-yl,1-methyl-benzimidazol-5-yl, pyridin-3-yl, oxazol-2-yl,oxazolidin-5-yl-2,4-dione, thiazolidin-5-yl-2,4-dione, isoxazol-3-yl,1,2,4-oxadiazol-3-yl-5-one, 1,3,4-oxadiazol-2-yl,5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl,5-isopropyl-1,3,4-oxadiazol-2-yl,5-(dimethylamino)-1,3,4-oxadiazol-2-yl, thiazol-2-yl,2-amino-thiazol-5-yl, 2-imino-thiazol-3-yl,5-amino-1,3,4-thiadiazol-2-yl, 5-(dimethylamino)-1,3,4-thiadiazol-2-yl,1,3,4-triazol-2-yl, 5-methyl-1,3,4-triazol-2-yl,2-amino-1,3,4-triazol-1-yl, 1-methyl-1,2,4-triazol-3-yl,1,2,4-triazol-5-yl, 3-amino-1,2,4-triazol-1-yl, 1,2,3,4-tetrazol-1-yl,1,2,3,4-tetrazol-5-yl and 1,2,3,5-tetrazol-4-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of azetidin-3-yl, pyrrolidin-3-yl,pyrrolidin-3-yl-2-one, R-pyrrolidin-3-yl-2-one, S-pyrrolidin-3-yl-2-one,3-methyl-pyrrolidin-3-yl-2-one, piperidin-1-yl-2-one,piperidin-3-yl-2-one, 1-(methylsulfonyl)-piperidin-4-yl,4-(methylsulfonyl)-piperazin-1-yl, morpholin-4-yl,thiomorpholin-4-yl-1,1-dioxide, tetrahydropyran-4-yl,tetrahydro-thiopyran-4-yl, tetrahydro-thiopyran-4-yl-1,1-dioxide,1,2-thiazinan-2-yl-1,1-dioxide, imidazol-2-yl, 5-methyl-imidazol-2-yl,4,5-dimethyl-imidazol-2-yl, 2-amino-imidazol-1-yl,imidazolidin-1-yl-2-one, 1-methyl-imidazolidin-5-yl-2,4-dione,2-(cyanoimino)-imidazolidin-1-yl, 1-methyl-benzimidazol-5-yl,pyridin-3-yl, oxazol-2-yl, oxazolidin-5-yl-2,4-dione,thiazolidin-5-yl-2,4-dione, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl-5-one,1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl,5-ethyl-1,3,4-oxadiazol-2-yl, 5-isopropyl-1,3,4-oxadiazol-2-yl,5-(dimethylamino)-1,3,4-oxadiazol-2-yl, thiazol-2-yl,2-amino-thiazol-5-yl, 2-imino-thiazol-3-yl,5-amino-1,3,4-thiadiazol-2-yl, 5-(dimethylamino)-1,3,4-thiadiazol-2-yl,1,3,4-triazol-2-yl, 2-amino-1,3,4-triazol-1-yl, 1,2,4-triazol-5-yl and1,2,3,4-tetrazol-5-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of pyrrolidin-3-yl-2-one,R-pyrrolidin-3-yl-2-one, S-pyrrolidin-3-yl-2-one,3-methyl-pyrrolidin-3-yl-2-one, piperidin-1-yl-2-one,piperidin-3-yl-2-one, 1-(methylsulfonyl)-piperidin-4-yl, morpholin-4-yl,thiomorpholin-4-yl-1,1-dioxide, tetrahydropyran-4-yl,tetrahydro-thiopyran-4-yl, tetrahydro-thiopyran-4-yl-1,1-dioxide,imidazol-2-yl, 4,5-dimethyl-imidazol-2-yl, imidazolidin-1-yl-2-one,1-methyl-imidazolidin-5-yl-2,4-dione, 1-methyl-benzimidazol-5-yl,pyridin-3-yl, oxazol-2-yl, oxazolidin-5-yl-2,4-dione,thiazolidin-5-yl-2,4-dione, isoxazol-3-yl, 1,3,4-oxadiazol-2-yl,5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl,5-(dimethylamino)-1,3,4-oxadiazol-2-yl, thiazol-2-yl,5-(dimethylamino)-1,3,4-thiadiazol-2-yl and 1,3,4-triazol-2-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of pyrrolidin-3-yl-2-one,S-pyrrolidin-3-yl-2-one, piperidin-1-yl-2-one,1-(methylsulfonyl)-piperidin-4-yl, morpholin-4-yl, tetrahydropyran-4-yl,tetrahydro-thiopyran-4-yl, tetrahydro-thiopyran-4-yl-1,1-dioxide,1-methyl-benzimidazol-5-yl, oxazol-2-yl, oxazolidin-5-yl-2,4-dione,isoxazol-3-yl and 5-(dimethylamino)-1,3,4-thiadiazol-2-yl.

In an embodiment, the present invention is directed to compounds offormula (II) wherein

is selected from the group consisting of naphth-2-yl, indol-5-yl,indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl,benzothiazol-5-yl, benzothiazol-6-yl, benzoisothiazol-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl and2,3-dihydro-benzo[b][1,4]dioxin-6-yl; wherein the naphth-2-yl,indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl,benzimidazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl,benzoisothiazol-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl; is optionally substituted on thephenyl portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, C₁₋₃alkyl, fluorinated C₁₋₂alkyl,C₁₋₃alkoxy and fluorinated C₁₋₂alkoxy; and wherein the naphth-2-yl,indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl,benzimidazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl,benzoisothiazol-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl is further optionally substitutedon the

portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, C₁₋₃alkyl, fluorinated C₁₋₂alkyl,C₁₋₃alkoxy and fluorinated C₁₋₂alkoxy.

In another embodiment, the present invention is directed to compounds offormula (II) wherein

is selected from the group consisting of naphth-2-yl and indazol-6-yl;wherein the naphth-2-yl or indazol-6-yl is optionally substituted oneither the phenyl or

portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen and C₁₋₃alkyl.

In another embodiment, the present invention is directed to compounds offormula (II) wherein

is selected from the group consisting of naphth-2-yl,6-fluoro-naphth-2-yl, 8-fluoro-naphth-2-yl and1-ethyl-4-fluoro-indazol-6-yl. In another embodiment, the presentinvention is directed to compounds of formula (II) wherein

is selected from the group consisting of naphth-2-yl,8-fluoro-naphth-2-yl and 1-ethyl-4-fluoro-indazol-6-yl.

In an embodiment, the present invention is directed to compounds offormula (II) wherein R³ is selected from the group consisting ofhydrogen, fluoro and C₁₋₂alkyl. In another embodiment, the presentinvention is directed to compounds of formula (II) wherein R³ ishydrogen.

In an embodiment, the present invention is directed to compounds offormula (II) wherein R⁴ is selected from the group consisting ofhydrogen, fluoro and C₁₋₂alkyl. In another embodiment, the presentinvention is directed to compounds of formula (II) wherein R⁴ ishydrogen.

In an embodiment, the present invention is directed to compounds offormula (II) wherein R⁵ is selected from the group consisting ofhydrogen, fluoro, hydroxy, C₁₋₄alkyl and —C(O)NR^(U)R^(V); wherein R^(U)and R^(V) are each independently selected from the group consisting ofhydrogen and C₁₋₂alkyl.

In an embodiment, the present invention is directed to compounds offormula (II) wherein R⁵ is selected from the group consisting ofhydrogen, hydroxy, fluoro, methyl, isopropyl and amino-carbonyl-. In anembodiment, the present invention is directed to compounds of formula(II) wherein R⁵ is selected from the group consisting of hydrogen,hydroxy, fluoro, methyl and isopropyl. In an embodiment, the presentinvention is directed to compounds of formula (II) wherein R⁵ isselected from the group consisting of hydrogen, hydroxy, fluoro, andisopropyl.

In an embodiment, the present invention is directed to compounds offormula (II) wherein

is a ring structure selected from the group consisting of cyclopentyl,cyclohexyl, azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl,piperidin-4-yl, morpholin-2-yl, tetrahydropyran-4-yl,4,5,6,7-tetrahydro-2H-indazol-5-yl, 1,5-dihydro-imidazol-5-yl,3,5-dihydro-imidazol-5-yl, 4,5-dihydro-imidazol-4-yl,4,5-dihydro-imidazol-5-yl, imidazolidin-4-yl, imidazolidin-5-yl,4,5-dihydro-pyrrol-3-yl, 4,5-dihydro-pyrazol-5-yl,1,2,5-thiadiazolidin-3-yl, 4,5,6,7-tetrahydro-benzo[d]isoxazol-5-yl,imidazo[1,2-a]imdazol-3-yl, imidazo[2,1-c][1,2,4]triazol-5-yl,6,7-dihydro-5H-imidazo[2,1-c][1,2,4]triazol-6-yl,tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-6-yl,6-oxabicyclo[3.2.1]octan-5-yl, 8-azabicyclo[3.2.1]octan-3-yl,6-azabicyclo[3.2.1]octan-4-yl, 1-oxa-3-azaspiro[4.5]decan-7-yl,2-azaspiro[4.5]decan-8-yl, 1λ²,3-diazaspiro[4.5]decan-7-yl,2-azaspiro[5.5]undecan-9-yl, 3-azaspiro[5.5]undecan-9-yl,1,3-diazaspiro[4.5]decan-8-yl and octahydro-cyclopenta[c]pyrrol-5-yl;wherein the

ring structure is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₄alkyl, hydroxy,oxo, thioxo, cyano, —NR^(F)R^(G), —NH(CN), ═NH, ═N(CN), ═N(OH),═N(O—C₁₋₂alkyl), —CH₂—NR^(F)R^(G)—C(O)—NR^(F)R^(G), —OC(O)—NR^(F)R^(G),—C(O)—CH₂OH, —SO₂—(C₁₋₄alkyl), —NR^(F)—SO₂—(C₁₋₄alkyl) and—C(NR^(F)R^(G))(═N—CN); and wherein R^(F) and R^(G) are eachindependently selected from the group consisting of hydrogen andC₁₋₄alkyl.

In another embodiment, the present invention is directed to compounds offormula (II) wherein

is selected from the group consisting of cyclopentyl,3-cyano-3-(aminocarbonyloxy)-cyclohex-1-yl,3-(aminocarbonyl)-3-hydroxy-cyclohex-1-yl,1-(isopropyl-sulfonyl)-azetidin-3-yl,1-(isopropyl-sulfonyl)-pyrrolidin-3-yl, piperidin-4-yl,1-(isopropyl-sulfonyl)-piperidin-3-yl,1-(methyl-sulfonyl)-piperidin-4-yl, 1-(ethyl-sulfonyl)-piperidin-4-yl,1-(isopropyl-sulfonyl)-piperidin-4-yl,1-(hydroxy-methyl-carbonyl)-piperidin-4-yl, morpholin-2-yl-3-one,tetrahydro-pyran-4-yl, 1-(isopropyl-sulfonyl)-4,5-dihydro-pyrrol-3-yl,2-(dimethylamino)-4,5-dihydro-imidazol-4-yl,1,5-dihydro-2-(cyanoamino)-imidazol-5-yl-4-one,3,5-dihydro-imidazol-5-yl-4-one,2-methyl-3,5-dihydro-imidazol-5-yl-4-one,2-(methylsulfonylamino)-4,5-dihydro-imidazol-5-yl,2-(cyanoimino)-4,5-dihydro-imidazol-5-yl, imidazolidin-5-yl-2-thione,2-imino-imidazolidin-4-yl, 2-(hydroxyimino)-imidazolidin-4-yl,2-(cyanoimino)-imidazolidin-4-yl, 2-(methoxyimino)-imidazolidin-4-yl,(Z)-2-(methoxyimino)-imidazolidin-4-yl,(E)-2-(methoxyimino)-imidazolidin-4-yl,(Z)-2-(methoxyimino)-imidazolidin-5-yl-4-one,5-oxo-2-thioxo-imidazolidin-4-yl, 4,5-dihydro-pyrazol-5-yl,4,5,6,7-tetrahydro-2H-indazol-5-yl,4,5,6,7-tetrahydro-benzo[d]isoxazol-5-yl,1,2,5-thiadiazolidin-3-yl-1,1-dioxide, imidazo[1,2-a]imdazol-3-yl-2-one,imidazo[2,1-c][1,2,4]triazol-5-yl-6-one,6,7-dihydro-5H-imidazo[2,1-c][1,2,4]triazol-6-yl,tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-6-yl-3-one,1-(isopropyl-amino-carbonyl)-octahydro-cyclopenta[c]pyrrol-5-yl,1-(1-(cyanoimino)-1-(isopropylamino)methyl)-octahydro-cyclopenta[c]pyrrol-5-yl,2-(isopropylsulfonyl)-octahydro-cyclopenta[c]pyrrol-5-yl,7-oxo-6-oxabicyclo[3.2.1]octan-5-yl,6-azabicyclo[3.2.1]octan-4-yl-7-one,8-(isopropylaminocarbonyl)-8-azabicyclo[3.2.1]octan-3-yl,8-(isopropylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl,(anti)-1-oxa-3-azaspiro[4.5]decan-7-yl-2,4-dione,(syn)-1-oxa-3-azaspiro[4.5]decan-7-yl-2,4-dione,1,3-diazaspiro[4.5]decan-8-yl-2,4-dione,1λ²,3-diazaspiro[4.5]decan-7-yl-2,4-dione,2-azaspiro[4.5]decan-8-yl-1-one, 2-azaspiro[5.5]undecan-9-yl-1-one and3-(isopropylsulfonyl)-3-azaspiro[5.5]undecan-9-yl.

In another embodiment, the present invention is directed to compounds offormula (II) wherein

is selected from the group consisting of cyclopentyl,3-cyano-3-(aminocarbonyloxy)-cyclohex-1-yl,3-(amino-carbonyl)-3-hydroxy-cyclohex-1-yl,1-(isopropyl-sulfonyl)-pyrrolidin-3-yl,1-(isopropyl-sulfonyl)-piperidin-3-yl,1-(methyl-sulfonyl)-piperidin-4-yl, 1-(ethyl-sulfonyl)-piperidin-4-yl,1-(isopropyl-sulfonyl)-piperidin-4-yl,1-(hydroxy-methyl-carbonyl)-piperidin-4-yl, morpholin-2-yl-3-one,tetrahydro-pyran-4-yl, 1-(isopropyl-sulfonyl)-4,5-dihydro-pyrrol-3-yl,1,5-dihydro-2-(cyanoamino)-imidazol-5-yl-4-one,2-(methylsulfonylamino)-4,5-dihydro-imidazol-5-yl,imidazolidin-5-yl-2-thione, 2-(cyanoimino)-4,5-dihydro-imidazol-5-yl,2-imino-imidazolidin-4-yl, 2-(hydroxyimino)-imidazolidin-4-yl,2-(cyanoimino)-imidazolidin-4-yl, 2-(methoxyimino)-imidazolidin-4-yl,(Z)-2-(methoxyimino)-imidazolidin-4-yl,(E)-2-(methoxyimino)-imidazolidin-4-yl,(Z)-2-(methoxyimino)-imidazolidin-5-yl-4-one,5-oxo-2-thioxo-imidazolidin-4-yl, 4,5,6,7-tetrahydro-2H-indazol-5-yl,imidazo[2,1-a]imdazol-3-yl-2-one,imidazo[2,1-c][1,2,4]triazol-5-yl-6-one,6,7-dihydro-5H-imidazo[2,1-c][1,2,4]triazol-6-yl,tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-6-yl-3-one,1-(isopropyl-amino-carbonyl)-octahydro-cyclopenta[c]pyrrol-5-yl,1-(1-(cyanoimino)-1-(isopropylamino)methyl)-octahydro-cyclopenta[c]pyrrol-5-yl,2-(isopropylsulfonyl)-octahydro-cyclopenta[c]pyrrol-5-yl,7-oxo-6-oxabicyclo[3.2.1]octan-5-yl,6-azabicyclo[3.2.1]octan-4-yl-7-one,8-(isopropyl-amino-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl,8-(isopropylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl,(anti)-1-oxa-3-azaspiro[4.5]decan-7-yl-2,4-dione,(syn)-1-oxa-3-azaspiro[4.5]decan-7-yl-2,4-dione,1,3-diazaspiro[4.5]decan-8-yl-2,4-dione,1λ²,3-diazaspiro[4.5]decan-7-yl-2,4-dione,2-azaspiro[4.5]decan-8-yl-1-one, 2-azaspiro[5.5]undecan-9-yl-1-one and3-(isopropylsulfonyl)-3-azaspiro[5.5]undecan-9-yl.

In another embodiment, the present invention is directed to compounds offormula (II) wherein

is selected from the group consisting of3-cyano-3-(aminocarbonyloxy)-cyclohex-1-yl,3-(amino-carbonyl)-3-hydroxy-cyclohex-1-yl,1-(isopropyl-sulfonyl)-pyrrolidin-3-yl,1-(isopropyl-sulfonyl)-piperidin-3-yl,1-(methyl-sulfonyl)-piperidin-4-yl, 1-(ethyl-sulfonyl)-piperidin-4-yl,1-(isopropyl-sulfonyl)-piperidin-4-yl, morpholin-2-yl-3-one,1-(isopropyl-sulfonyl)-4,5-dihydro-pyrrol-3-yl,1,5-dihydro-2-(cyanoamino)-imidazol-5-yl-4-one,2-(cyanoimino)-4,5-dihydro-imidazol-5-yl,2-(cyanoimino)-imidazolidin-4-yl, 2-(methoxyimino)-imidazolidin-4-yl,(Z)-2-(methoxyimino)-imidazolidin-4-yl,(E)-2-(methoxyimino)-imidazolidin-4-yl,(Z)-2-(methoxyimino)-imidazolidin-5-yl-4-one,5-oxo-2-thioxo-imidazolidin-4-yl, 4,5,6,7-tetrahydro-2H-indazol-5-yl,imidazo[2,1-a]imdazol-3-yl-2-one,1-(isopropyl-amino-carbonyl)-octahydro-cyclopenta[c]pyrrol-5-yl,1-(1-(cyanoimino)-1-(isopropylamino)methyl)-octahydro-cyclopenta[c]pyrrol-5-yl,7-oxo-6-oxabicyclo[3.2.1]octan-5-yl,6-azabicyclo[3.2.1]octan-4-yl-7-one,8-(isopropylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl,(anti)-1-oxa-3-azaspiro[4.5]decan-7-yl-2,4-dione,(syn)-1-oxa-3-azaspiro[4.5]decan-7-yl-2,4-dione,imidazo[2,1-a]imdazol-3-yl-2-one,1λ²,3-diazaspiro[4.5]decan-7-yl-2,4-dione,2-azaspiro[4.5]decan-8-yl-1-one, 2-azaspiro[5.5]undecan-9-yl-1-one and3-(isopropylsulfonyl)-3-azaspiro[5.5]undecan-9-yl.

In another embodiment, the present invention is directed to compounds offormula (II) wherein

is selected from the group consisting of3-(amino-carbonyl)-3-hydroxy-cyclohex-1-yl,1-(isopropyl-sulfonyl)-pyrrolidin-3-yl,1-(isopropyl-sulfonyl)-piperidin-3-yl,1-(isopropyl-sulfonyl)-piperidin-4-yl, morpholin-2-yl-3-one,1-(isopropyl-sulfonyl)-4,5-dihydro-pyrrol-3-yl,1,5-dihydro-2-(cyanoamino)-imidazol-5-yl-4-one,2-(cyanoimino)-4,5-dihydro-imidazol-5-yl,(Z)-2-(methoxyimino)-imidazolidin-4-yl,(E)-2-(methoxyimino)-imidazolidin-4-yl,(Z)-2-(methoxyimino)-imidazolidin-5-yl-4-one,5-oxo-2-thioxo-imidazolidin-4-yl, 6-azabicyclo[3.2.1]octan-4-yl-7-one,8-(isopropylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl,(anti)-1-oxa-3-azaspiro[4.5]decan-7-yl-2,4-dione,(syn)-1-oxa-3-azaspiro[4.5]decan-7-yl-2,4-dione,imidazo[2,1-a]imdazol-3-yl-2-one,1λ²,3-diazaspiro[4.5]decan-7-yl-2,4-dione,2-azaspiro[4.5]decan-8-yl-1-one, 2-azaspiro[5.5]undecan-9-yl-1-one and3-(isopropylsulfonyl)-3-azaspiro[5.5]undecan-9-yl.

In another embodiment, the present invention is directed to compounds offormula (II) wherein

is selected from the group consisting of3-(amino-carbonyl)-3-hydroxy-cyclohex-1-yl,1-(isopropyl-sulfonyl)-pyrrolidin-3-yl,1-(isopropyl-sulfonyl)-piperidin-3-yl, morpholin-2-yl-3-one,1-(isopropyl-sulfonyl)-4,5-dihydro-pyrrol-3-yl,1,5-dihydro-2-(cyanoamino)-imidazol-5-yl-4-one,2-(cyanoimino)-4,5-dihydro-imidazol-5-yl,(Z)-2-(methoxyimino)-imidazolidin-4-yl,(Z)-2-(methoxyimino)-imidazolidin-5-yl-4-one,5-oxo-2-thioxo-imidazolidin-4-yl, 6-azabicyclo[3.2.1]octan-4-yl-7-one,imidazo[2,1-a]imdazol-3-yl-2-one,1λ²,3-diazaspiro[4.5]decan-7-yl-2,4-dione and2-azaspiro[5.5]undecan-9-yl-1-one.

In another embodiment, the present invention is directed to compounds offormula (II) wherein

is selected from the group consisting of1-(isopropyl-sulfonyl)-piperidin-3-yl,1,5-dihydro-2-(cyanoamino)-imidazol-5-yl-4-one,2-(cyanoimino)-4,5-dihydro-imidazol-5-yl,(Z)-2-(methoxyimino)-imidazolidin-4-yl,(Z)-2-(methoxyimino)-imidazolidin-5-yl-4-one,6-azabicyclo[3.2.1]octan-4-yl-7-one andimidazo[2,1-a]imdazol-3-yl-2-one,1λ²,3-diazaspiro[4.5]decan-7-yl-2,4-dione.

In an embodiment, the present invention is directed to compounds offormula (III) wherein

is selected from the group consisting of naphth-2-yl, indol-5-yl,indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl,benzothiazol-5-yl, benzothiazol-6-yl, benzoisothiazol-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl and2,3-dihydro-benzo[b][1,4]dioxin-6-yl; wherein the naphth-2-yl,indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl,benzimidazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl,benzoisothiazol-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl is optionally substituted on thephenyl portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, C₁₋₃alkyl, fluorinated C₁₋₂alkyl,C₁₋₃alkoxy and fluorinated C₁₋₂alkoxy; and wherein the naphth-2-yl,indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl,benzimidazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl,benzoisothiazol-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl is further optionally substitutedon the

portion of the

bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, C₁₋₃alkyl, fluorinated C₁₋₂alkyl,C₁₋₃alkoxy and fluorinated C₁₋₂alkoxy.

In another embodiment, the present invention is directed to compounds offormula (III) wherein

is selected from the group consisting of naphth-2-yl, benzothiazol-5-yl,benzothiazol-6-yl, 3,4-dihydro-benzo[b][1,4]oxazin-6-yl and3,4-dihydro-benzo[b][1,4]oxazin-7-yl; wherein the naphth-2-yl,benzothiazol-5-yl, benzothiazol-6-yl,3,4-dihydro-benzo[b][1,4]oxazin-6-yl or3,4-dihydro-benzo[b][1,4]oxazin-7-yl is optionally substituted on thephenyl or

portion of the

with a substituent selected from the group consisting of halogen,C₁₋₃alkyl and C₁₋₂alkoxy.

In another embodiment, the present invention is directed to compounds offormula (II) wherein

is selected from the group consisting of naphth-2-yl,6-fluoro-naphth-2-yl, 8-fluoro-naphth-2-yl, 6-methoxy-naphth-2-yl,benzothiazol-5-yl, benzothiazol-6-yl,4-methyl-3,4-dihydro-benzo[b][1,4]oxazin-6-yl and4-methyl-3,4-dihydro-benzo[b][1,4]oxazin-7-yl.

In another embodiment, the present invention is directed to compounds offormula (III) wherein

is selected from the group consisting of naphth-2-yl and8-fluoro-naphth-2-yl.

In an embodiment, the present invention is directed to compounds offormula (III) wherein R⁶ is selected from the group consisting ofhydrogen, fluoro and C₁₋₂alkyl. In another embodiment, the presentinvention is directed to compounds of formula (III) wherein R⁶ ishydrogen.

In an embodiment, the present invention is directed to compounds offormula (III) wherein R⁷ is selected from the group consisting ofhydrogen, fluoro and C₁₋₂alkyl. In another embodiment, the presentinvention is directed to compounds of formula (III) wherein R⁷ ishydrogen.

In an embodiment, the present invention is directed to compounds offormula (III) wherein Y is selected from the group consisting of—CR^(H)R^(J)— and —CR^(H)R^(J)—CHR^(K)—; wherein R^(H) and R^(J) areeach independently selected from the group consisting of hydrogen,halogen, hydroxy, C₁₋₄alkyl, fluorinated C₁₋₂alkyl, C₃₋₆cycloalkyl andC₅₋₆cycloalkenyl; provided that when one of R^(H) or R^(J) isC₃₋₆cycloalkyl or C₅₋₆cycloalkenyl, then the other of R^(H) or R^(J) ishydrogen; and wherein R^(K) is selected from the group consisting ofhydrogen and C₁₋₄alkyl; alternatively, when Y is —CR^(H)R^(J)—, thenR^(H) and R^(J) may be taken together with the carbon atom to which theyare bound to form C₅₋₆cycloalkyl.

In another embodiment, the present invention is directed to compounds offormula (III) wherein Y is —CR^(H)R^(J)—, and R^(H) and R^(J) may betaken together with the carbon atom to which they are bound to formC₅₋₆cycloalkyl.

In another embodiment, the present invention is directed to compounds offormula (III) wherein Y is selected from the group consisting of—CR^(H)R^(J)— and —CR^(H)R^(J)—CHR^(K)—; wherein R^(H) and R^(J) areeach independently selected from the group consisting of hydrogen,halogen, hydroxy, C₁₋₄alkyl and C₅₋₆cycloalkenyl; provided that when oneof R^(H) or R^(J) is C₅₋₆cycloalkenyl, then the other of R^(H) or R^(J)is hydrogen; and wherein R^(K) is selected from the group consisting ofhydrogen and C₁₋₄alkyl.

In another embodiment, the present invention is directed to compounds offormula (III) wherein Y is selected from the group consisting of—CH(isopropyl), —C(OH)(isopropyl)-, —C(F)(isopropyl)-,—C(methyl)(isopropyl)-, —CH(cyclohex-1-en-1-yl), —CH(isopropyl)-CH₂— and—CH₂—CH(isopropyl)-.

In another embodiment, the present invention is directed to compounds offormula (III) wherein Y is selected from the group consisting of—CH(isopropyl), —C(OH)(isopropyl)-, —C(F)(isopropyl)-,—CH(isopropyl)-CH₂— and —CH₂—CH(isopropyl)-. In another embodiment, thepresent invention is directed to compounds of formula (III) wherein Y isselected from the group consisting of —CH(isopropyl),—C(OH)(isopropyl)-, —CH(isopropyl)-CH₂— and —CH₂—CH(isopropyl)-. Inanother embodiment, the present invention is directed to compounds offormula (III) wherein Y is selected from the group consisting of—CH(isopropyl), —C(OH)(isopropyl)- and —CH(isopropyl)-CH₂—. In anotherembodiment, the present invention is directed to compounds of formula(III) wherein Y is selected from the group consisting of —CH(isopropyl),and —CH(isopropyl)-CH₂—.

In an embodiment, the present invention is directed to compounds offormula (III) wherein Z is selected from the group consisting of—C(O)—NR^(L)R^(M), —C(O)—NH—OR^(N), —C(O)—NH—SO₂—R^(N);—C(O)—NH(CH(CH₂OH)₂), —C(O)—NH(C(CH₂OH)₃), —C(O)—NH—(CH₂CH₂O)_(a)—R^(N),—C(O)—NH—CH(CH₂O—(CH₂CH₂O)_(b)—R^(N))₂,—C(O)—NH—C(CH₂O—(CH₂CH₂O)_(b)—R^(N))₃), —C(O)—NH—CH₂CH₂—NR^(P)R^(Q),—C(O)—NH—(CH₂CH₂O)_(a)—CH₂CH₂—NR^(P)R^(Q), —NR^(S)—C(O)—NR^(P)R^(Q),—NR^(S)—C(O)—NH—CH₂CH₂—NR^(P)R^(Q) and —NR^(S)—C(NH₂)═N—CN; wherein a isan integer from 1 to 4; wherein b is an integer from 0 to 3; whereinR^(L) and R^(M) are each independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; wherein R^(N) is selected from thegroup consisting of hydrogen and C₁₋₂alkyl; wherein R^(P) and R^(Q) areeach independently selected from the group consisting of hydrogen andC₁₋₂alkyl; and wherein R^(S) is selected from the group consisting ofhydrogen and C₁₋₂alkyl.

In another embodiment, the present invention is directed to compounds offormula (III) wherein Z is selected from the group consisting of—C(O)—NR^(L)R^(M), —C(O)—NH—OR^(N), —C(O)—NH—SO₂—R^(N);—C(O)—NH(CH(CH₂OH)₂), —C(O)—NH(C(CH₂OH)₃), —C(O)—NH—(CH₂CH₂O)_(a)—R^(N),—C(O)—NH—CH₂CH₂—NR^(P)R^(Q), —C(O)—NH—(CH₂CH₂O)_(a)—CH₂CH₂—NR^(P)R^(Q),—NR^(S)—C(O)—NR^(P)R^(Q), —NR^(S)—C(O)—NH—CH₂CH₂—NR^(P)R^(Q) and—NR^(S)—C(NH₂)═N—CN; wherein a is an integer from 1 to 3; wherein R^(L)and R^(M) are each independently selected from the group consisting ofhydrogen and C₁₋₄alkyl; wherein R^(N) is selected from the groupconsisting of hydrogen and methyl; wherein R^(P) and R^(Q) are eachindependently selected from the group consisting of hydrogen and methyl;and wherein R^(S) is selected from the group consisting of hydrogen andmethyl.

In another embodiment, the present invention is directed to compounds offormula (III) wherein a is an integer from 1 to 3. In anotherembodiment, the present invention is directed to compounds of formula(III) wherein a is an integer from 1 to 2.

In another embodiment, the present invention is directed to compounds offormula (III) wherein b is an integer from 0 to 2. In anotherembodiment, the present invention is directed to compounds of formula(III) wherein b is an integer from 1 to 2.

In another embodiment, the present invention is directed to compounds offormula (III) wherein R^(L) and R^(M) are each independently selectedfrom the group consisting of hydrogen and C₁₋₄alkyl. In anotherembodiment, the present invention is directed to compounds of formula(III) wherein R^(L) and R^(M) are each independently selected from thegroup consisting of hydrogen, methyl and ethyl. In another embodiment,the present invention is directed to compounds of formula (III) whereinR^(L) and R^(M) are each independently selected from the groupconsisting of hydrogen and methyl.

In another embodiment, the present invention is directed to compounds offormula (III) wherein P^(N) is selected from the group consisting ofhydrogen and methyl.

In another embodiment, the present invention is directed to compounds offormula (III) wherein R^(P) and R^(Q) are each independently selectedfrom the group consisting of hydrogen and methyl.

In another embodiment, the present invention is directed to compounds offormula (III) wherein R^(S) is selected from the group consisting ofhydrogen and methyl.

In another embodiment, the present invention is directed to compounds offormula (III) wherein Z is selected from the group consisting of—C(O)—NH₂, —C(O)—NH(isopropyl), —C(O)—NH(OCH₃), —C(O)—NH(CH(CH₂OH)₂),—C(O)—NH(C(CH₂OH)₃), —C(O)—NH—CH₂CH₂—N(CH₃)₂, —C(O)—NH—CH₂CH₂OH,—C(O)—NH—CH₂CH₂O—CH₂CH₂—N(CH₃)₂,—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂—N(CH₃)₂,—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂O—CH₃, —C(O)—NH—SO₂—CH₃, —NH—C(O)—NH₂,—N(CH₃)—C(O)—NH₂, —NH—C(O)—NH—CH₂CH₂—N(CH₃)₂ and —NH-(E)-C(NH₂)═N—CN;

In another embodiment, the present invention is directed to compounds offormula (III) wherein Z is selected from the group consisting of—C(O)—NH₂, —C(O)—NH(isopropyl), —C(O)—NH(OCH₃), —C(O)—NH(CH(CH₂OH)₂),—C(O)—NH(C(CH₂OH)₃), —C(O)—NH—CH₂CH₂OH, —C(O)—NH—CH₂CH₂O—CH₂CH₂—N(CH₃)₂,—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂—N(CH₃)₂,—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂O—CH₃, —NH—C(O)—NH₂, and—NH-(E)-C(NH₂)═N—CN.

In another embodiment, the present invention is directed to compounds offormula (III) wherein Z is selected from the group consisting of—C(O)—NH₂, —C(O)—NH(isopropyl), —C(O)—NH(OCH₃), —C(O)—NH(CH(CH₂OH)₂),—C(O)—NH—CH₂CH₂OH, —C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂O—CH₃, —NH—C(O)—NH₂,and —NH-(E)-C(NH₂)═N—CN.

In another embodiment, the present invention is directed to compounds offormula (III) wherein Z is selected from the group consisting of—C(O)—NH₂, —C(O)—NH(isopropyl), —C(O)—NH(OCH₃), —C(O)—NH—CH₂CH₂OH and—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂O—CH₃.

In certain embodiments,

is other than indol-5-yl, indol-6-yl, indazol-5-yl, indazol-6-yl,benzimidazol-5-yl or benzimidazol-5-yl; wherein the indol-5-yl,indol-6-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl orbenzimidazol-5-yl is optionally substituted with one or more (forexample one to three, one to two or one) substituents independentlyselected from the group consisting of halogen, C₁₋₃alkyl andC₃₋₆cycloalkyl.

In certain embodiments,

is other than indol-5-yl, indol-6-yl, indazol-5-yl, indazol-6-yl,benzimidazol-5-yl or benzimidazol-5-yl; wherein the indol-5-yl,indol-6-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl orbenzimidazol-5-yl is optionally substituted with one or more (forexample one to three, one to two or one) substituents independentlyselected from the group consisting of halogen, C₁₋₃alkyl andC₃₋₆cycloalkyl.

In certain embodiments,

is other than indol-5-yl, indol-6-yl, indazol-5-yl, indazol-6-yl,benzimidazol-5-yl or benzimidazol-5-yl; wherein the indol-5-yl,indol-6-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl orbenzimidazol-5-yl is optionally substituted with one or more (forexample one to three, one to two or one) substituents independentlyselected from the group consisting of halogen, C₁₋₃alkyl andC₃₋₆cycloalkyl.

In certain embodiments of the present invention,

is other than benzimidazol-5-yl. In certain embodiments of the presentinvention,

is other than indazol-6-yl.

In certain embodiments of the present invention,

is other than benzimidazol-5-yl. In certain embodiments of the presentinvention,

is other than indazol-6-yl.

In certain embodiments of the present invention,

is other than benzimidazol-5-yl. In certain embodiments of the presentinvention,

is other than indazol-6-yl.

In certain embodiments,

is other than azabicyclo[3.2.1]octan-3-yl.

In certain embodiments,

is other than pyrrolidin-3-yl-2-one or piperidin-3-yl-2-one.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e.

R¹, R², X,

R³, R⁴, R⁵,

R⁶, R⁷, Y, Z, etc.) are independently selected to be any individualsubstituent or any subset of substituents independently selected fromthe complete list as defined herein.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e.

R¹, R², X,

R³, R⁴, R⁵,

R⁶, R⁷, Y, Z, etc.) are independently selected to be any individualsubstituent or any subset of substituents independently selected fromthe substituents listed in Tables 1-3 below. In certain embodiments, thepresent invention is directed to any single compound or subset ofcompounds selected from the representative compounds listed in Tables1-3 below.

Representative compounds of the present invention are as listed in Table1 to 3, below. Unless otherwise noted, wherein a double bond is presentin the listed compound, the compound was prepared as either E or Zconfiguration. Where a stereogenic center is present in the listedcompound, the compound was prepared as a racemic mixture. Where astereogenic center is present, and the compound was prepared in anenantiomeric excess of a particular stereo-isomer, the S*- and R*designations are intended to indicate that the exactstereo-configuration of the center has not been determined. Where twostereogenic centers are present, the compound was prepared as aparticular diastereomeric isomer, where the syn and anti designationsare intended to indicate that relative stereo-configurations of twocenters of the racemic mixtures and the exact stereo-configuration ofthe centers has not been determined.

TABLE 1 Representative Compounds of Formula (I)

ID No.

R¹ R²

1 8-fluoro- H H —C(methyl)₂—CH₂— oxazolidin-5-yl-2,4-dione naphth-2-yl 28-fluoro- H H —C(methyl)₂-(Z)—CH═ oxazolidin-5-yl-2,4-dione naphth-2-yl3 1-ethyl-4- H H —C(ethyl)₂- 1,2,3,4-tetrazol-5-yl fluoro-indazol- 6-yl4 1-ethyl-4- H H —C(ethyl)₂- 1,2,4-oxadiazol-3-yl-5-one fluoro-indazol-6-yl 5 1-ethyl-4- H H —C(ethyl)₂- 1,3,4-triazol-2-yl fluoro-indazol-6-yl 6 8-fluoro- H H —C(ethyl)₂-(E)-CH═ oxazolidin-5-yl-2,4-dionenaphth-2-yl 7 8-fluoro- H H -cyclopent-1,1-yl-CH₂—oxazolidin-5-yl-2,4-dione naphth-2-yl 8 8-fluoro- H H-cyclopent-1,1-yl-(E)-CH═ oxazolidin-5-yl-2,4-dione naphth-2-yl 98-fluoro- H H —C(ethyl)₂-CH₂— oxazolidin-5-yl-2,4-dione naphth-2-yl 105,7-difluoro- H H -cyclopent-1,1-yl-(E)-CH═ oxazolidin-5-yl-2,4-dionenaphth-2-yl 11 8-fluoro- H H -cycloprop-1,1,-yl-(E)-CH═oxazolidin-5-yl-2,4-dione naphth-2-yl 12 1-ethyl-4- H H—C(ethyl)₂-(E)-CH═ oxazolidin-5-yl-2,4-dione fluoro-indazol- 6-yl 131-ethyl-4- H H —C(ethyl)₂-(E)-CH═ pyrrolidin-3-yl-2-one fluoro-indazol-6-yl 14 2-ethyl-4- H H —C(ethyl)₂-(E)-CH═ oxazolidin-5-yl-2,4-dionefluoro-indazol- 5-yl 15 1-ethyl-4- H H —C(ethyl)₂-CH₂—1,3,4-triazol-2-yl fluoro-indazol- 6-yl 16 1-ethyl-4- H H—C(ethyl)₂-(E)-CH═ pyrrolidin-3-yl-2-one fluoro-indazol- 6-yl 174-ethyl-8- H H —C(ethyl)₂-CH₂— pyrrolidin-3-yl-2-one fluoro-3,4-dihydro-2H- benzo[b]1,4] oxazin-6-yl 18 2,2-dimethyl- H H—C(ethyl)₂-(Z)-CH═ oxazolidin-5-yl-2,4-dione chromen-7-yl 198-isopropyl- H H —C(ethyl)₂-(E)-CH═ oxazolidin-5-yl-2,4-dionenaphth-2-yl 20 1-ethyl-4- H H —C(ethyl)₂-CH₂— imidazol-2-ylfluoro-indazol- 6-yl 21 1-ethyl-4- H H —C(ethyl)₂-5-methyl-1,3,4-triazol- fluoro-indazol- 2-yl 6-yl 22 4-ethyl-8- H H—C(ethyl)₂- 1,3,4-triazol-2-yl fluoro-3,4- dihydro-2H- benzo[b][1,4]oxazin-6-yl 23 8- H H —C(ethyl)₂-(Z)-CH═ oxazolidin-5-yl-2,4-dionetrifluoromethyl- naphth-2-yl 24 1-ethyl-4- H H —C(ethyl)₂-1-methyl-1,3,4-triazol- fluoro-indazol- 5-yl 6-yl 25 4-ethyl-8- H H—C(ethyl)₂-(E)-CH═ pyrrolidin-3-yl-2-one fluoro-3,4- dihydro-2H-benzo[b][1,4] oxazin-6-yl 26 1-ethyl-4- H H —C(ethyl)₂-1-methyl-1,3,4-triazol- fluoro-indazol- 5-yl 6-yl 27 1-ethyl-4- H H—C(ethyl)₂- 1-methyl-1,2,4-triazol- fluoro-indazol- 3-yl 6-yl 282,2-dimethyl- H H —C(ethyl)₂-(Z)-CH═ oxazolidin-5-yl-2,4-dione2H-chromen-7- yl 29 1-ethyl-4- H H —C(ethyl)₂- isoxazol-3-ylfluoro-indazol- 6-yl 30 1-ethyl-4- H H —C(ethyl)₂- oxazol-2-ylfluoro-indazol- 6-yl 31 1-ethyl-4- H H —C(ethyl)₂- imidazol-2-ylfluoro-indazol- 6-yl 32 6,8-difluoro- H H —C(ethyl)₂-(E)-CH═oxazolidin-5-yl-2,4-dione naphth-2-yl 33 6,8-difluoro- H H —C(ethyl)₂-1,3,4-triazol-2-yl naphth-2-yl 34 1-ethyl-3- H H —C(ethyl)₂-(E)-CH═oxazolidin-5-yl-2,4-dione methyl- indazol-6-yl 35 4-ethyl-3,4- H H—C(ethyl)₂-(E)-CH═ oxazolidin-5-yl-2,4-dione dihydro-2H- benzo[b][1,4]oxazin-6-yl 36 1-ethyl-4- fluoro H —C(ethyl)₂- 1,3,4-triazol-2-ylfluoro-indazol- 6-yl 37 1-ethyl-4- fluoro H —C(ethyl)₂- oxazol-2-ylfluoro-indazol- 6-yl 38 1-ethyl-4- H H —C(ethyl)₂- 5-isopropyl-1,3,4-fluoro-indazol- oxadiazol-2-yl 6-yl 39 5,7-difluoro- H H —C(ethyl)₂-1,3,4-triazol-2-yl naphth-2-yl 40 1-ethyl-4- H H —C(ethyl)₂-CH₂—pyrrolidin-3-yl-2-one fluoro-indazol- 6-yl 41 1-ethyl-4- H H—C(ethyl)₂-CH₂— oxazol-2-yl fluoro-indazol- 6-yl 42 1-ethyl-4- H H—C(ethyl)₂- 1,3,4-triazol-2-yl fluoro-indazol- 6-yl 43 1-ethyl-5- H H—C(ethyl)₂-(E)-CH═ oxazolidin-5-yl-2,4-dione methyl- indazol-6-yl 444-ethyl-3,4- H H —C(ethyl)₂-CH₂— oxazolidin-5-yl-2,4-dione dihydro-2H-benzo[b][1,4] oxazin-6-yl 45 1-ethyl-4- H H —C(ethyl)₂-5-trifluoromethyl- fluoro-indazol- 1,3,4-oxadiazol-2-yl 6-yl 461-ethyl-4- fluoro H —C(ethyl)₂-CH₂— 1,5-dihydro-2H-pyrrol-fluoro-indazol- 3-yl-2-one 6-yl 47 1-ethyl-4- fluoro H—C(ethyl)₂-(E)-CH═ pyrrolidin-3-yl-2-one fluoro-indazol- 6-yl 481-ethyl-4- H H —C(ethyl)₂- 5-(dimethylamino)- fluoro-indazol-1,3,4-thiadiazol-2-yl 6-yl 49 8-ethyl-naphth- H H —C(ethyl)₂-(E)-CH═oxazolidin-5-yl-2,4-dione 2-yl 50 6,8-difluoro- H H —C(ethyl)₂-imidazol-2-yl naphth-2-yl 51 1-ethyl-4- H H —C(ethyl)₂- 5-amino-1,3,4-fluoro-indazol- oxadiazol-2-yl 6-yl 52 1-ethyl-4- H H —C(ethyl)₂-5-amino-1,3,4- fluoro-indazol- thiadazol-2-yl 6-yl 53 1-ethyl-4- H H—C(ethyl)₂- 5-ethyl-1,3,4- fluoro-indazol- oxadiazol-2-yl 6-yl 541-ethyl-5- H H —C(ethyl)₂-(E)-CH═ oxazolidin-5-yl-2,4-dionefluoro-indazol- 6-yl 55 1-ethyl-4- H H —C(ethyl)₂-(Z)-CH═oxazolidin-5-yl-2,4-dione fluoro-indazol- 6-yl 56 1-ethyl-4- H H—C(ethyl)₂-CH₂— oxazolidin-5-yl-2,4-dione fluoro-indazol- 6-yl 571-ethyl-4- H H —C(ethyl)₂- 5-(dimethylamino)- fluoro-indazol-1,3,4-oxadiazol-2-yl 6-yl 58 1-ethyl-4- H H —C(ethyl)₂-CH₂—piperidin-3-yl-2-one fluoro-indazol- 6-yl 59 8-fluoro- H H-(syn)-CH(isopropyl)- oxazolidin-5-yl-2,4-dione naphth-2-yl 60 8-fluoro-H H -(anti)-CH(isopropyl)- oxazolidin-5-yl-2,4-dione naphth-2-yl 61naphth-2-yl H H —CH(isopropyl)- 1,2,3,5-tetrazol-4-yl 62 8-fluoro- H H—CH(isopropyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dione naphth-2-yl 638-fluoro- H H —CH(isopropyl)-(Z)-CH═ thiazolidin-5-yl-2,4-dionenaphth-2-yl 64 8-fluoro- H H -(syn)-CH(isopropyl)-CH₂—thiazolidin-5-yl-2,4-dione naphth-2-yl 65 8-fluoro- H H-(anti)-CH(isopropyl)-CH₂— thiazolidin-5-yl-2,4-dione naphth-2-yl 668-fluoro- H H —CH(isopropyl)-CH₂— morpholin-4-yl naphth-2-yl 678-fluoro- H H —CH(isopropyl)- 4,5-dimethyl-imidazol- naphth-2-yl 2-yl 688-fluoro- H H —CH(isopropyl)- 2-amino-thiazol-5-yl naphth-2-yl 698-fluoro- H H —CH(isopropyl)- 1-methyl-imidazolidin- naphth-2-yl5-yl-2,4-dione 70 8-fluoro- H H —CH(isopropyl)-CH₂—1,2,3,5-tetrazol-4-yl naphth-2-yl 71 8-fluoro- H H —CH(isopropyl)-thiazolidin-5-yl-2,4-dione naphth-2-yl 72 8-fluoro- H H—CH(isopropyl)-CH₂— 1,2,4-oxadiazol-3-yl- naphth-2-yl 5-one 73 8-fluoro-H H —CH(isopropyl)-CH₂— 1-methyl-imidazolidin- naphth-2-yl5-yl-2,4-dione 74 8-fluoro- H H -(anti)-CH(isopropyl)-CH₂—oxazolidin-5-yl-2,4-dione naphth-2-yl 75 8-fluoro- methyl H—CH(isopropyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dione naphth-2-yl 768-fluoro- H H —CH(isopropyl)- imidazol-2-yl naphth-2-yl 77 8-fluoro- H H—CH(isopropyl)-CH₂— oxazolidin-5-yl-2,4-dione naphth-2-yl 78 8-fluoro- HH —CH(R*- oxazolidin-5-yl-2,4-dione naphth-2-yl isopropyl)-(Z)-CH═ 798-fluoro- H H —CH(S*- oxazolidin-5-yl-2,4-dione naphth-2-ylisopropyl)-(Z)-CH═ 80 8-fluoro- H H —CH(isopropyl)-(E)-CH═1-methyl-imidazolidin- naphth-2-yl 5-yl-2,4-dione 81 8-fluoro- H H-(syn)-CH(isopropyl)-CH₂— oxazolidin-5-yl-2,4-dione naphth-2-yl 828-fluoro- methyl H —CH(isopropyl)- imidazol-2-yl naphth-2-yl 838-fluoro- bromo H —CH(isopropyl)- oxazolidin-5-yl-2,4-dione naphth-2-yl(Z)-CH═ 84 8-fluoro- H H —CH(isopropyl)-(E)- oxazolidin-5-yl-2,4-dionenaphth-2-yl C(methyl)═ 85 2,3- H H —CH(isopropyl)-(Z)-CH═oxazolidin-5-yl-2,4-dione dihydrobenzo [b][1,4]dioxin- 6-yl 862-ethyl-4- H H —CH(isopropyl)-CH₂— oxazolidin-5-yl-2,4-dione methyl-2H-indazol-6-yl 87 1-ethyl-4- H H —CH(isopropyl)-CH₂—oxazolidin-5-yl-2,4-dione fluoro-indazol- 6-yl 88 8-fluoro- H H—CH(isopropyl)-(E)-CH═ 1-methyl-imidazolidin- naphth-2-yl 5-yl-2,4-dione89 8-fluoro- H H —CH(isopropyl)-CH₂— oxazolidin-5-yl-2,4-dionenaphth-2-yl 90 1-ethyl-4- H H —CH(isopropyl)-(Z)-CH═oxazolidin-5-yl-2,4-dione fluoro-indazol- 6-yl 91 1-ethyl-7- H H—CH(isopropyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dione fluoro- benzimidazol-6-yl 92 8-fluoro- H H —CH(cyclopentyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dionenaphth-2-yl 93 benzo- H H —CH(isopropyl)-(Z)-CH═oxazolidin-5-yl-2,4-dione isothiazol-6-yl 94 1-ethyl-4- H H—CH(isopropyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dione fluoro-indazol- 6-yl 958-fluoro- H H —CH(isopropyl)- 1,2,4-oxadiazol-3-yl- naphth-2-yl 5-one 968-fluoro- H H —CH(isopropyl)-(Z)- oxazolidin-5-yl-2,4-dione naphth-2-ylC(methyl)═ 97 1-methyl-7- H H —CH(isopropyl)-(Z)-CH═oxazolidin-5-yl-2,4-dione chloro- benzimidazol- 5-yl 98 2-ethyl-4- H H—CH(isopropyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dione methyl-2H- indazol-6-yl99 1-ethyl-4- H H —CH(isopropyl)-CH═ 1,2,4-oxadiazol-3-yl-fluoro-indazol- 5-one 6-yl 100 8-fluoro- H H —CH(isopropyl)-CH₂—1,2,4-oxadiazol-3-yl- naphth-2-yl 5-one 101 8-fluoro- H H—CH(isopropyl)-CH₂— 4-(methyl-sulfonyl)- naphth-2-yl piperazin-1-yl 1028-fluoro- methyl H —CH(isopropyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dionenaphth-2-yl 103 8-fluoro- H H —CH(cyclopropyl)-(Z)-CH═oxazolidin-5-yl-2,4-dione naphth-2-yl 104 4-ethyl-3,4- H H—CH(isopropyl)-CH₂— thiomorpholin-4-yl dihydro-2H- 1,1-dioxidebenzo[b][1,4] oxazin-6-yl 105 8-fluoro- H H —CH(n-pent-3-yl)-(E)-CH═oxazolidin-5-yl-2,4-dione naphth-2-yl 106 1-ethyl-4- H H—CH(isopropyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dione fluoro-indazol- 6-yl107 1-methyl-7- H H —CH(isopropyl)-CH₂— oxazolidin-5-yl-2,4-dionechloro- benzimidazol- 5-yl 108 4-methyl-3,4- H H —CH(isopropyl)-(Z)-CH═oxazolidin-5-yl-2,4-dione dihydro-2H- benzo[b][1,4] oxazin-6-yl 1091-ethyl-4- H H —CH(isopropyl)-CH₂— 4-(methyl-sulfonyl)- fluoro-indazol-piperazin-1-yl 6-yl 110 2-ethyl-4- H H —CH(isopropyl)-CH₂—oxazolidin-5-yl-2,4-dione methyl-2H- indazol-6-yl 111 1-ethyl-4- methylH —CH(isopropyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dione fluoro-indazol- 6-yl112 8-fluoro- methyl H —CH(isopropyl)-(Z)-CH₂— oxazolidin-5-yl-2,4-dionenaphth-2-yl 113 8-fluoro- H H —CH(isopropyl)- oxazolidin-5-yl-2,4-dionenaphth-2-yl (Z)-C(methyl)═ 114 8-fluoro- H H —CH(isopropyl)-oxazolidin-5-yl-2,4-dione naphth-2-yl (E)-C(methyl)═ 115 8-fluoro- H H—CH(isopropyl)-CH₂— piperidin-1-yl-2-one naphth-2-yl 116 1-ethyl-4- H H—CH(isopropyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dione chloro-indazol- 6-yl117 8-fluoro- H H —CH(benzyl)-(E)-CH═ oxazolidin-5-yl-2,4-dionenaphth-2-yl 118 1-methyl-indol- H H —CH(isopropyl)-(Z)-CH═oxazolidin-5-yl-2,4-dione 5-yl 119 8-fluoro- H H —CH(isopropyl)-CH₂—thiomorpholin-4-yl naphth-2-yl 1,1-dioxide 120 2-ethyl- H H—CH(isopropyl)-CH₂— oxazolidin-5-yl-2,4-dione indazol-6-yl 1214-ethyl-3,4- H H —CH(isopropyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dionedihydro-2H- benzo[b][1,4] oxazin-6-yl 122 1-isopropyl-4- H H—CH(isopropyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dione fluoro-indazol- 6-yl123 8-fluoro- H H —CH(phenyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dionenaphth-2-yl 124 1-cyclopentyl- H H —CH(isopropyl)-(Z)-CH═oxazolidin-5-yl-2,4-dione 4-fluoro- indazol-6-yl 125 1-ethyl-4- chloro H—CH(isopropyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dione fluoro-indazol- 6-yl126 1-ethyl-4- H H —CH(isopropyl)-CH₂— oxazolidin-5-yl-2,4-dione methyl-indazol-6-yl 127 1-ethyl-4- H H —CH(cyclohexyl)-(E)-CH═oxazolidin-5-yl-2,4-dione fluoro-indazol- 6-yl 128 4-ethyl-3,4- H H—CH(isopropyl)-CH₂— thiomorpholin-4-yl dihydro-2H- 1,1-dioxidebenzo[b][1,4] oxazin-6-yl-3- one 129 4-ethyl-3,4- H H—CH(isopropyl)-CH₂— thiomorpholin-4-yl dihydro-2H- 1,1-dioxidebenzo[b][1,4] oxazin-6-yl 130 1-ethyl-4- H H —CH(cyclopentyl)-(E)-CH═oxazolidin-5-yl-2,4-dione fluoro-indazol- 6-yl 131 8-fluoro- H H—CH(isopropyl)- 5-methyl-imidazol-2-yl naphth-2-yl 132 8-fluoro- H H—CH(isopropyl)- imidazolidin-5-yl-2,4-dione naphth-2-yl 133 1-ethyl-4- HH —CH(isopropyl)-CH₂— thiomorpholin-4-yl fluoro-indazol- 1,1-dioxide6-yl 134 8-fluoro- H H —CH(cyclohexyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dionenaphth-2-yl 135 8-isopropyl- H H —CH(isopropyl)-(Z)-CH═oxazolidin-5-yl-2,4-dione naphth-2-yl 136 8-fluoro- chloro H—CH(isopropyl)-(Z)-CH═ oxazolidin-5-yl-2,4-dione naphth-2-yl 1374-ethyl-3,4- H H —CH(isopropyl)-CH═ oxazolidin-5-yl-2,4-dionedihydro-2H- benzo[b][1,4] oxazin-6-yl 138 8-fluoro- H H —CH(isopropyl)-1,2,4-triazol-5-yl- naphth-2-yl 139 8-fluoro- H H —CH(isopropyl)-CH₂—1,2,4-triazol-5-yl- naphth-2-yl 140 8-fluoro- H H —CH(isopropyl)-CH₂—imidazol-2-yl naphth-2-yl 141 8-ethyl-naphth- H H —CH(isopropyl)-(Z)-CH═oxazolidin-5-yl-2,4-dione 2-yl 142 8-cyano- H H —CH(isopropyl)-(Z)-CH═oxazolidin-5-yl-2,4-dione naphth-2-yl 143 8- H H —CH(isopropyl)-(Z)-CH═oxazolidin-5-yl-2,4-dione trifluoromethyl- naphth-2-yl 144 8-fluoro- H H-(syn)-CH(S- R-pyrrolidin-3-yl-2- naphth-2-yl isopropyl)-CH₂— one 1458-fluoro- H H -(anti)-CH(S- S-pyrrolidin-3-yl-2-one naphth-2-ylisopropyl)-CH₂— 146 1-ethyl-4- H H —CH(isopropyl)-CH₂—3-methyl-pyrrolidin-3- fluoro-indazol- yl-2-one 6-yl 147 1-ethyl-4- H H-(syn)-CH(S- R-pyrrolidin-3-yl-2- fluoro-indazol- isopropyl)-CH₂— one6-yl 148 1-ethyl-4- H H -(anti)-CH(S- S-pyrrolidin-3-yl-2-onefluoro-indazol- isopropyl)-CH₂— 6-yl 149 8-fluoro- H H—CH(isopropyl)-(E)-CH═ pyrrolidin-3-yl-2-one naphth-2-yl 150 8-fluoro- HH —CH(isopropyl)-(Z)-CH═ pyrrolidin-3-yl-2-one naphth-2-yl 1511-ethyl-4- H H —CH(isopropyl)-CH₂— pyrrolidin-3-yl-2-one fluoro-indazol-6-yl 154 8-fluoro- H H —CH(isopropyl)- imidazolidin-1-yl-2-onenaphth-2-yl 157 8-fluoro- H H —CH(isopropyl)- 2-(imino)-thiazol-3-ylnaphth-2-yl 158 8-fluoro- H H —CH(isopropyl)-NH— thiazol-2-ylnaphth-2-yl 159 8-fluoro- H H —CH(isopropyl)-NH— 1,3,4-triazol-2-ylnaphth-2-yl 160 8-fluoro- H H —CH(isopropyl)- 2-amino-1,3,4-triazol-naphth-2-yl 1-yl 161 8-fluoro- H H —CH(isopropyl)-3-amino-1,2,4-triazol- naphth-2-yl 1-yl 162 8-fluoro- H H—CH(isopropyl)- 2-amino-imidazol-1-yl naphth-2-yl 163 8-fluoro- H H—CH(isopropyl)- 1,2-thiazinan-2-yl-1,1- naphth-2-yl dioxide 1644-ethyl-3,4- H H —CH(isopropyl)- thiomorpholin-4-yl dihydro-2H-benzo[b][1,4] oxazin-6-yl 165 8-fluoro- H H —CH(isopropyl)- cyclohexylnaphth-2-yl NH—SO₂— 166 8-fluoro- H H —CH(isopropyl)-piperidin-1-yl-2-one naphth-2-yl 168 1-ethyl-4- H H —CH(isopropyl)-thiomorpholin-4-yl- fluoro-indazol- 1,1-dioxide 6-yl 169 4-ethyl-3,4- HH —CH(isopropyl)- thiomorpholin-4-yl- dihydro-2H- 1,1-dioxidebenzo[b][1,4] oxazin-6-yl 170 8-fluoro- H H —CH(isopropyl)-2-(cyanoimino)- naphth-2-yl imidazolidin-1-yl 171 1-ethyl-4- H H—CH(isopropyl)- 1,2,3,4-tetrazol-1-yl fluoro-indazol- 6-yl 1721-ethyl-4- H H —CH(isopropyl)- 1,3,4-triazol-1-yl fluoro-indazol- 6-yl173 8-fluoro- H H —CF(isopropyl)- 3,5-difluoro-phenyl naphth-2-ylC(O)—NH—SO₂— 174 8-fluoro- H H —CH(isopropyl)- tetrahydro-pyran-4-ylnaphth-2-yl C(O)—NH— 175 8-fluoro- H H —CH(isopropyl)-4,5-dichloro-thien-2-yl naphth-2-yl C(O)—NH—SO₂— 176 8-fluoro- H H—CH(isopropyl)- thiazol-2-yl naphth-2-yl C(O)—NH— 177 8-fluoro- H H—CH(isopropyl)- azetidin-3-yl naphth-2-yl C(O)—NH— 178 8-fluoro- H H—CH(isopropyl)- pyrrolidin-3-yl naphth-2-yl C(O)—NH— 179 8-fluoro- H H—CH(isopropyl)- tetrahydro-thiopyran- naphth-2-yl C(O)—NH—4-yl-1,1-dioxide 180 8-fluoro- H H —CH(isopropyl)- pyridin-3-ylnaphth-2-yl C(O)—NH— 181 8-fluoro- H H —CH(isopropyl)- 1-methyl-naphth-2-yl C(O)—NH— benzimidazol-5-yl 182 8-fluoro- H H —CH(isopropyl)-1-methyl-azetidin-3-yl naphth-2-yl C(O)—NH— 183 8-fluoro- H H—CH(isopropyl)- tetrahydro-thiopyran- naphth-2-yl C(O)—NH— 4-yl 1848-fluoro- H H —CH(isopropyl)- 1-(methyl-sulfonyl)- naphth-2-yl C(O)—NH—piperidin-4-yl 252 8-fluoro- H H —CH₂— oxazolidin-5-yl-2,4- naphth-2-yldione 254 8-fluoro- H H —CH(isopropyl)- thiazol-2-yl naphth-2-ylCH₂—C(O)—NH— 256 8-fluoro- H H —CH(isopropyl)- 4,5-dichloro-thien-2-ylnaphth-2-yl CH₂—C(O)—NH—SO₂— 261 8-fluoro- H H —CH(isopropyl)-imidazol-2-yl naphth-2-yl CH₂—C(O)—NH— 262 8-fluoro- H H —CH₂—5-isopropyl- naphth-2-yl imidazolidin-5-yl-2,4- dione 263 8-fluoro- H H—CH₂— 5-isopropyl- naphth-2-yl oxazolidin-5-yl-2,4- dione 264 8-fluoro-H H —CH(isopropyl)- imidazolidin-5-yl-2,4- naphth-2-yl dione 2708-fluoro- H H —CH₂—CH(isopropyl)- 1,2,3,4-tetrazol-5-yl naphth-2-yl 2711-ethyl-4- H H —C(ethyl)₂- 5-methyl-1,3,4- fluoro-indazol-oxadiazol-2-yl 6-yl 272 8-fluoro- chloro H —CH₂—CH(isopropyl)-1,2,4-oxadiazol-3-yl- naphth-2-yl 5-one 273 8-fluoro- H H—CH(isopropyl)- cyclohexyl naphth-2-yl CH₂—SO₂— 274 8-fluoro- H H—CH(isopropyl)- oxazolidin-5-yl-2,4- naphth-2-yl (Z)-CH═ dione 2758-fluoro- H H —CH(t-butyl)-(E)-CH═ oxazolidin-5-yl-2,4- naphth-2-yldione 276 2,2-difluoro- H H —CH(isopropyl)- oxazolidin-5-yl-2,4-benzo[d][1,3] (Z)-CH═ dione dioxol-5-yl 277 1-ethyl-4- H H—CH(isopropyl)- 1,2,4-oxadiazol-3-yl- fluoro-1H- 5-one indazol-6-yl 2784-ethyl-3,4- H H —CH(isopropyl)- 1,2,4-oxadiazol-3-yl- dihydro-2H- 5-onebenzo[b][1,4] oxazin-6-yl 279 6,8-difluoro- H H —C(ethyl)₂-1,3,4-triazol-2-yl- naphth-2-yl 280 naphth-2-yl H H —CH(-carbonyl-cyclohex-1-en-1-yl oxy-ethyl)- 281 naphth-2-yl H H —C(-carbonyl-oxy-cyclohexyl ethyl)═ 303 8-fluoro- H H -(Z)-C(isopropyl)═oxazolidin-5-yl-2,4- naphth-2-yl dione 304 8-fluoro- H H-(E)-C(isopropyl)═ oxazolidin-5-yl-2,4- naphth-2-yl dione 305 8-fluoro-H H -(E)-C(isopropyl)═ thiazolidin-5-yl-2,4- naphth-2-yl dione 3068-fluoro- H H —CH₂-(E)- oxazolidin-5-yl-2,4- naphth-2-yl C(isopropyl)═dione 307 8-fluoro- H H —CH₂—CH(isopropyl)- imidazol-2-yl naphth-2-yl308 8-fluoro- H H —CH₂—CH(isopropyl)- oxazolidin-5-yl-2,4- naphth-2-yldione 309 8-fluoro- H H —CH₂—CH(isopropyl)- 1,3,4-triazol-2-ylnaphth-2-yl 310 8-cyano- H H —CH(isopropyl)-(E)-CH═ oxazolidin-5-yl-2,4-naphth-2-yl dione

TABLE 2 Representative Compounds of Formula (II)

ID No.

R³ R⁴ R⁵

152 naphth-2-yl H H methyl imidazo[2,1-c][1,2,4]triazol- 5-yl-6-one 153naphth-2-yl H H methyl imidazo[1,2-a]imidazol-3-yl- 2-one 1558-fluoro-naphth- H H isopropyl imidazo[1,2-a]imidazol-3-yl- 2-yl 2-one156 8-fluoro-naphth- H H isopropyl imidazo[2,1-c][1,2,4]triazol- 2-yl5-yl-6-one 167 naphth-2-yl H H methyl 6,7-dihydro-5H-imidazo[2,1-c][1,2,4]triazol- 6-yl 185 naphth-2-yl H H H 3-cyano-3-(aminocarbonyloxy)- cyclohex-1-yl 186 naphth-2-yl H H H1-(methyl-sulfonyl)- piperidin-4-yl 187 naphth-2-yl H H H4,5,6,7-tetrahydro- benzo[d]isoxazol-5-yl 188 naphth-2-yl H H H(anti)-1-oxa-3- azaspiro[4.5]decan-7-yl- 2,4-dione 189 naphth-2-yl H H H(syn)-1-oxa-3- azaspiro[4.5]decan-7-yl- 2,4-dione 190 naphth-2-yl H H H1-(ethyl-sulfonyl)-piperidin- 4-yl 191 naphth-2-yl H H H1λ²,3-diazaspiro[4.5]decan- 7-yl-2,4-dione 192 naphth-2-yl H H Htetrahydro-pyran-4-yl 194 naphth-2-yl H H H piperidin-4-yl 195naphth-2-yl H H H 4,5,6,7-tetrahydro-2H- indazol-5-yl 1961-ethyl-4-fluoro- H H H 2-azaspiro[5.5]undecan-9- indazol-6-yl yl-1-one197 naphth-2-yl H H H 1-(hydroxymethyl- carbonyl)-piperidin-4-yl 1981-ethyl-4-fluoro- H H H 1-(isopropyl-sulfonyl)- indazol-6-ylpiperidin-4-yl 199 6-fluoro-naphth- H H H 1-(isopropyl-sulfonyl)- 2-ylpiperidin-4-yl 200 naphth-2-yl H H H 1-(isopropyl-sulfonyl)-piperidin-4-yl 201 naphth-2-yl H H H 3-(aminocarbonyl)-3-hydroxy-cyclohex-1-yl 203 naphth-2-yl H H H 1,3-diazaspiro[4.5]decan-8-yl-2,4-dione 204 1-ethyl-4-fluoro- H H H 3-(isopropyl-sulfonyl)-3-indazol-6-yl azaspiro[5.5]undecan-9-yl 205 1-ethyl-4-fluoro- H H H2-(isopropyl-sulfonyl)- indazol-6-yl octahydro- cyclopenta[c]pyrrol-5-yl206 1-ethyl-4-fluoro- H H H 8-(isopropyl-sulfonyl)-8- indazol-6-ylazabicyclo[3.2.1]octan-3-yl 207 1-ethyl-4-fluoro- H H H2-azaspiro[4.5]decan-8-yl- indazol-6-yl 1-one 208 1-ethyl-4-fluoro- H HH 8-(isopropyl-amino- indazol-6-yl carbonyl)-8-azabicyclo[3.2.1]octan-3-yl 209 1-ethyl-4-fluoro- H H H1-(isopropyl-amino- indazol-6-yl carbonyl)-octahydro-cyclopenta[c]pyrrol-5-yl 210 1-ethyl-4-fluoro- H H H1-(1-(cyanoimino)-1- indazol-6-yl (isopropylamino)methyl)- octahydro-cyclopenta[c]pyrrol-5-yl 211 1-ethyl-4-fluoro- H H H1-(isopropyl-sulfonyl)- indazol-6-yl piperidin-3-yl 2131-ethyl-4-fluoro- H H H 1-(isopropyl-sulfonyl)- indazol-6-ylpyrrolidin-3-yl 214 1-ethyl-4-fluoro- H H H 1-(isopropyl-sulfonyl)-indazol-6-yl azetidin-3-yl 215 1-ethyl-4-fluoro- H H H tetrahydro-1H,3H-indazol-6-yl pyrrolo[1,2-c]oxazol-6-yl-3- one 219 naphth-2-yl H H amino-cyclopentyl carbonyl 222 naphth-2-yl H H methyl3,5-dihydro-imidazol-5-yl-4- one 223 naphth-2-yl H H methyl2-methyl-3,5-dihydro- imidazol-5-yl-4-one 236 8-fluoro-naphth- H Hisopropyl 1,5-dihydro-2- 2-yl (cyanoamino)-imidazol-5- yl-4-one 2378-fluoro-naphth- H H isopropyl (Z)-2-(methoxyimino)- 2-ylimidazolidin-5-yl-4-one 247 naphth-2-yl H H amino-4,5-dihydro-pyrazol-5-yl carbonyl- 248 1-ethyl-4-fluoro- H H isopropylmorpholin-2-yl-3-one indazol-6-yl 282 naphth-2-yl H H methyl1,2,5-thiadiazolidin-3-yl- 1,1-dioxide 283 naphth-2-yl H H methyl2-(cyanoimino)- imidazolidin-4-yl 285 naphth-2-yl H H methyl2-(methoxyimino)- imidazolidin-4-yl 286 naphth-2-yl H H methylimidazolidin-5-yl-2-thione 287 naphth-2-yl H H methyl2-imino-imidazolidin-4-yl 288 naphth-2-yl H H methyl 2-(hydroxyimino)-imidazolidin-4-yl 289 naphth-2-yl H H methyl 2-(dimethylamino)-4,5-dihydro-imidazol-4-yl 290 naphth-2-yl H H methyl2-(methyl-sulfonyl-amino)- 4,5-dihydro-imidazol-5-yl 2918-fluoro-naphth- H H isopropyl 2-(cyanoimino)-4,5- 2-yldihydro-imidazol-5-yl 292 8-fluoro-naphth- H H isopropyl(Z)-2-(methoxyimino)- 2-yl imidazolidin-4-yl 293 8-fluoro-naphth- H Hisopropyl (E)-2-(methoxyimino)- 2-yl imidazolidin-4-yl 2948-fluoro-naphth- H H isopropyl 5-oxo-2-thioxo- 2-yl imidazolidin-4-yl295 1-ethyl-4-fluoro- H H hydroxy 1-(isopropyl-sulfonyl)- indazol-6-ylpiperidin-3-yl 296 1-ethyl-4-fluoro- H H fluoro 1-(isopropyl-sulfonyl)-indazol-6-yl piperidin-3-yl 297 1-ethyl-4-fluoro- H H H1-(isopropyl-sulfonyl)-4,5- indazol-6-yl dihydro-pyrrol-3-yl 2981-ethyl-4-fluoro- H H hydroxy 1-(isopropyl-sulfonyl)- indazol-6-ylazetidin-3-yl 299 1-ethyl-4-fluoro- H H H 7-oxo-6-oxabicyclo[3.2.1]indazol-6-yl octan-5-yl 300 1-ethyl-4-fluoro- H H hydroxy6-azabicyclo[3.2.1]octan- indazol-6-yl 4-yl-7-one

TABLE 3 Representative Compounds of Formula (Ill)

ID No.

R⁶ R⁷ Y Z 216 8-fluoro-naphth- H H —C(F)(isopropyl)- —C(O)—NH₂ 2-yl 217naphth-2-yl H H —C(F)(isopropyl)- —C(O)—NH₂ 218 naphth-2-yl H H —C(OH)—C(O)—NH₂ (isopropyl)- 220 naphth-2-yl H H —CH(isopropyl)- —C(O)—NH₂ 221naphth-2-yl H H —CH(isopropyl)- —C(O)—NH—SO₂—CH₃ 224 naphth-2-yl H H—C(F)(isopropyl)- —C(O)—NH—SO₂—CH₃ 225 4-methyl-3,4- H H —C(OH)—C(O)—NH₂ dihydro-2H- (isopropyl)- benzo[b][1,4] oxazin-7-yl 226naphth-2-yl H H —CH(cyclohexen- —C(O)—NH₂ 1-yl) 227 8-fluoro-naphth- H H—CH(isopropyl)- —C(O)—NH—CH₂CH₂—N(CH₃)₂ 2-yl 228 8-fluoro-naphth- H H—CH(isopropyl)- —C(O)—NH(OCH₃) 2-yl 229 8-fluoro-naphth- H H—CH(isopropyl)- —C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂—N(CH₃)₂ 2-yl 2308-fluoro-naphth- H H —CH(isopropyl)- —C(O)—NH(CH(CH₂OH)₂) 2-yl 2318-fluoro-naphth- H H —CH(isopropyl)- —C(O)—NH(C(CH₂OH)₃) 2-yl 232naphth-2-yl H H —C(methyl) —C(O)—NH₂ (isopropyl)- 233 8-fluoro-naphth- HH —CH(isopropyl)- —C(O)—NH—CH₂CH₂O—CH₂CH₂—N(CH₃)₂ 2-yl 2348-fluoro-naphth- H H —CH(isopropyl)- —C(O)—NH—CH₂CH₂—OH 2-yl 2388-fluoro-naphth- H H —CH(isopropyl)-—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂O—CH₃ 2-yl 239 8-fluoro-naphth- H H—CH(isopropyl)- —C(O)—NH(isopropyl) 2-yl 241 6-methoxy- H H—CH(isopropyl)- —C(O)—NH—CH₂CH₂—N(CH₃)₂ naphth-2-yl 242 6-fluoro-naphth-H H —CH(isopropyl)- —C(O)—NH—CH₂CH₂—N(CH₃)₂ 2-yl 243 benzothiazol-5- H H—CH(isopropyl)- —C(O)—NH—CH₂CH₂—N(CH₃)₂ yl 244 4-methyl-3,4- H H—CH(isopropyl)- —C(O)—NH—CH₂CH₂—N(CH₃)₂ dihydro-2H- benzo[b][1,4]oxazin-7-yl 246 benzothiazol-6- H H —CH(isopropyl)-—C(O)—NH—CH₂CH₂—N(CH₃)₂ yl 249 naphth-2-yl H H —CH(isopropyl)- —C(O)—NH₂CH₂— 250 naphth-2-yl H H —CH(isopropyl)- —C(O)—NH—SO₂—CH₃ CH₂— 2518-fluoro-naphth- H H —CH(isopropyl)- —C(O)—NH₂ 2-yl CH₂— 2538-fluoro-naphth- H H —CH₂—CH(isopropyl)- —C(O)—NH₂ 2-yl 2558-fluoro-naphth- H H —C(OH) —C(O)—NH₂ 2-yl (isopropyl)- 2578-fluoro-naphth- H H —CH(isopropyl)- —C(O)—NH(OCH₃) 2-yl CH₂— 2588-fluoro-naphth- H H —CH(isopropyl)- —C(O)—NH—CH₂CH₂—OH 2-yl CH₂— 2598-fluoro-naphth- H H —-CH(isopropyl)- —C(O)—NH—CH₂CH₂—N(CH₃)₂ 2-yl CH₂—260 8-fluoro-naphth- H H —CH(isopropyl)- —C(O)—NH(isopropyl)- 2-yl CH₂—265 8-fluoro-naphth- H H —CH(isopropyl)- —N(CH₃)—C(O)—NH₂ 2-yl 2668-fluoro-naphth- H H —CH(isopropyl)- —NH—C(O)—NH—CH₂CH₂—N(CH₃)₂ 2-yl 2678-fluoro-naphth- H H —CH(isopropyl)- —NH—C(O)—NH₂ 2-yl 2688-fluoro-naphth- H H —CH(isopropyl)- —NH-(E)—C(NH₂)═N—CN 2-yl 3024-methyl-3,4- H H —CH(isopropyl)- —C(O)-NH—CH₂CH₂—N(CH₃)₂ dihydro-benzo[b][1,4] oxazin-6-yl

In an embodiment, the present invention is directed to a compound offormula (I) selected from the group consisting of

-   6-(1-ethyl-4-fluoro-indazol-6-yl)-3-[1-ethyl-1-(1H-tetrazol-5-yl)propyl]-1H-pyridin-2-one,    Compound #3;-   6-(1-ethyl-4-fluoro-indazol-6-yl)-3-[1-ethyl-1-(4H-1,2,4-triazol-3-yl)propyl]-1H-pyridin-2-one,    Compound #5;-   (5E)-5-[2-ethyl-2-[6-(8-fluoro-2-naphthyl)-2-oxo-1H-pyridin-3-yl]butylidene]oxazolidine-2,4-dione,    Compound #6;-   6-(1-ethyl-4-fluoro-indazol-6-yl)-3-[1-ethyl-1-[(E)-(2-oxopyrrolidin-3-ylidene)methyl]propyl]-1H-pyridin-2-one,    Compound #16;-   6-(1-ethyl-4-fluoro-indazol-6-yl)-3-[1-ethyl-1-(5-methyl-4H-1,2,4-triazol-3-yl)propyl]-1H-pyridin-2-one,    Compound #21;-   6-(1-ethyl-4-fluoro-indazol-6-yl)-3-(1-ethyl-1-oxazol-2-yl-propyl)-1H-pyridin-2-one,    Compound #30;-   6-(1-ethyl-4-fluoro-indazol-6-yl)-3-[1-ethyl-1-(1H-imidazol-2-yl)propyl]-1H-pyridin-2-one,    Compound #31;-   (5Z)-5-[2-ethyl-2-[6-(1-ethyl-4-fluoro-indazol-6-yl)-2-oxo-1H-pyridin-3-yl]butylidene]oxazolidine-2,4-dione,    Compound #55;-   (5Z)-5-[2-[6-(8-fluoro-2-naphthyl)-2-oxo-1H-pyridin-3-yl]-3-methyl-butylidene]oxazolidine-2,4-dione,    Compound #62;-   (5Z)-5-[2-[6-(8-fluoro-2-naphthyl)-5-methyl-2-oxo-1H-pyridin-3-yl]-3-methyl-butylidene]oxazolidine-2,4-dione,    Compound #75;

and tautomers and pharmaceutically acceptable salts thereof.

In certain embodiments, the present invention is directed to a compoundof formula (I), compounds of formula (II) and/or compounds of formula(III); wherein the compound has a measured K_(i) (nM) according to theEP3 competition binding assay procedure taught in Biological Example 1,which follows herein, or less than about 500 nM, preferably less thanabout 250 nM, more preferably less than about 100 nM, more preferablyless than about 50 nM, more preferably less than about 25 nM, morepreferably less than about 10 nM, more preferably less than about 5 nM,more preferably less than about 2 nM.

Definitions

As used herein, unless otherwise noted, “halogen” shall mean chlorine,bromine, fluorine and iodine. Preferably, the halogen is fluorine,chlorine or bromine, more preferably fluorine.

As used herein when referring to a substituent group, unless otherwisenoted, the term “oxo” shall mean a double bonded oxygen group, i.e. asubstituent group of the formula ═O.

As used herein, unless otherwise noted, the term “thioxo” shall mean adouble bonded sulfur group, i.e. a substituent group of the formula ═S.

As used herein, unless otherwise noted, the term “imino” shall mean adouble bonded nitrogen group, i.e. a substituent group of the formula═NH. One skilled in the art will recognize that wherein said nitrogenatom is substituted, the corresponding group shall be named as asubstituted imino. For example, a substituent group of the formula ═N—CNshall be referred to herein as cyanoimino, a substituent group of theformula ═N—OH shall be referred to herein as hydroxyimino, a substituentgroup of the formula ═N—OCH₃ shall be referred to herein asmethoxyimino, etc.

As used herein, unless otherwise noted, the term “C_(X-Y)alkyl” whereinX and Y are integers, whether used alone or as part of a substituentgroup, shall include straight and branched chains of between X and Ycarbon atoms. For example, C₁₋₄alkyl shall include straight and branchedchains of between one and four carbon atoms including methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl.

One skilled in the art will recognize that the terms “—(C_(X-Y)alkyl)-and —C_(X-Y)alkyl-” wherein X and Y are integers, shall denote anyC_(X-Y)alkyl carbon chain as herein defined, wherein said C_(X-Y)alkylchain is divalent and is further bound through two points of attachment,preferably through two terminal carbon atoms.

As used herein, unless otherwise noted, the term “fluorinatedC_(X-Y)alkyl” wherein X and Y are integers, shall mean any C_(X-Y)alkylgroup as defined above substituted with at least one fluoro atom,preferably one to three fluoro atoms.

Suitable examples include but are not limited to —CF₃, —CH₂—CF₃,—CF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, “C_(X-Y)alkoxy” wherein X and Yare integers, whether used alone or as part of a substituent group,shall denote an oxygen ether radical of the above described C_(X-Y)alkylstraight or branched chain alkyl group. For example, C₁₋₄alkoxy shallinclude oxygen ether radicals of straight and branched alkyl chains ofbetween one and four carbon atoms including methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, sec-butoxy and t-butoxy.

As used herein, unless otherwise noted, the term “fluorinatedC_(X-Y)alkoxy” wherein X and Y are integers, shall denote an oxygenether radical as defined described, substituted with at least one fluoroatom, preferably one to three fluoro atoms. Suitable examples includebut are not limited to —OCF₃, —OCH₂—CF₃, —OCF₂—CF₂—CF₂—CF₃, and thelike.

As used herein, unless otherwise noted, the term “C_(X-Y)cycloalkyl”wherein X and Y are integers, shall mean any stable monocyclic,bicyclic, polycyclic or bridged, saturated ring system consisting ofbetween X and Y carbon atom. For example, the term C₃₋₆cycloalkyl shallinclude cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, unless otherwise noted, the term “C_(X-Y)cycloalkenyl”wherein X and Y are integers, shall mean any stable monocyclic,bicyclic, polycyclic or bridged, partially unsaturated ring systemconsisting of between X and Y carbon atom. For example, the termC₃₋₆cycloalkenyl shall include cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, and the like.

The term “four to six membered monocyclic heterocyclyl” shall denote anyfour or six membered monocyclic ring structure, wherein the ringstructure may be saturated, partially unsaturated or aromatic, andwherein the ring structure contains at least one heteroatom selectedfrom the group consisting of O, N and S, optionally containing one tothree additional heteroatoms independently selected from the groupconsisting of O, N and S. The four to six membered monocyclicheterocyclyl group may be attached at any heteroatom or carbon atom ofthe ring such that the result is a stable structure. Suitable examplesof four to six membered monocyclic heterocyclylgroups include, but arenot limited to azetidinyl, pyrrolidinyl, pyrrolinyl, furanyl, thienyl,pyrrolyl, isopuyrrolyl, pyrazlyl, imidazolyl, isoimidazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,dioxazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, dioxalanyl,imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, pyrazinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, tetrahydrothiopyranyl, thiazinanyl, triazinyl,oxazinyl, isoxazinyl, and the like.

Preferably, the four to six membered monocyclic heterocyclyl is selectedfrom the group consisting of azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl,thiopyranyl, tetrahydro-thiopyranyl, thiazinanyl, imidazolyl,imidazolidinyl, benzimidazolyl, 1,5-dihydro-pyrrolyl, thienyl,pyridinyl, oxazolyl, oxazolidinyl, thiazolyl, isoxazolyl, oxadiazolyl,thiazolyl, thiadiazolyl, triazolyl, and tetrazolyl. More preferably, thefour to six membered monocyclic heterocyclyl is selected from the groupconsisting of azetidin-3-yl, pyrrolidin-3-yl, piperidin-1-yl,piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, tetrahydropyran-4-yl, thiopyran-4-yl,tetrahydro-thiopyran-4-yl, 1,2-thiazinan-2-yl, imidazol-2-yl,imidazol-2-yl, imidazol-1-yl, imidazolidin-1-yl, imidazolidin-5-yl,benzimidazol-5-yl, 1,5-dihydro-pyrrol-3-yl, thien-2-yl, pyridin-3-yl,oxazol-2-yl, oxazol-5-yl, oxazolidin-5-yl, thiazol-5-yl, isoxazol-3-yl,1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, thiazol-2-yl, thiazol-5-yl,thiazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-triazol-2-yl,1,3,4-triazol-5-yl, 1,3,4-triazol-1-yl, 1,2,4-triazol-5-yl,1,2,4-triazol-1-yl and 1,2,3,4-tetrazol-5-yl.

The term “nine to ten membered bicyclic heterocyclyl” shall denote anynine or ten membered bicyclic ring structure, wherein the ring structuremay be saturated, partially unsaturated, partially aromatic, benzo-fusedor aromatic, and wherein the ring structure contains at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The nine to ten memberedbicyclic heterocyclyl group may be attached at any heteroatom or carbonatom of the ring such that the result is a stable structure. Suitableexamples of nine to ten membered bicyclic heterocyclyl groups include,but are not limited to indolizinyl, indolyl, isoindolinyl, indazolyl,benzofuryl, benzoxazolyl, anthracil, benzopyranyl, quinolinyl,isoquinolinyl, cinnolinyl, quinazolinyyl, benzothienyl, benzimidazolyl,benzothiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, benzofuryl, isobenzofuryl, indolinyl,chromanyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl,oxetanyl, pyrido[3,4-b]pyridine, purinyl, quinozilinyl, quinoxalinyl,quinazolinyl, benzo[b][1,4]oxazinyl, 3,4-dihydro-benzo[b][1,4]oxazinyl,benzo[b][1,4]dioxinyl, 2,3-dihydro-benzo[b][1,4]dioxinyl, and the like.

When a particular group is “substituted” (e.g., alkyl, cycloalkyl,heterocyclyl, etc.), that group may have one or more substituents,preferably from one to five substituents, more preferably from one tothree substituents, most preferably from one to two substituents,independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

As used herein, the notation “*” shall denote the presence of astereogenic center.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Preferably, wherein the compound is present as an enantiomer, theenantiomer is present at an enantiomeric excess of greater than or equalto about 80%, more preferably, at an enantiomeric excess of greater thanor equal to about 90%, more preferably still, at an enantiomeric excessof greater than or equal to about 95%, more preferably still, at anenantiomeric excess of greater than or equal to about 98%, mostpreferably, at an enantiomeric excess of greater than or equal to about99%. Similarly, wherein the compound is present as a diastereomer, thediastereomer is present at an diastereomeric excess of greater than orequal to about 80%, more preferably, at an diastereomeric excess ofgreater than or equal to about 90%, more preferably still, at andiastereomeric excess of greater than or equal to about 95%, morepreferably still, at an diastereomeric excess of greater than or equalto about 98%, most preferably, at an diastereomeric excess of greaterthan or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of thepresent invention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe present invention may form solvates with water (i.e., hydrates) orcommon organic solvents, and such solvates are also intended to beencompassed within the scope of this invention.

Furthermore, it is intended that within the scope of the presentinvention, any element, in particular when mentioned in relation to acompound of formula (I), shall comprise all isotopes and isotopicmixtures of said element, either naturally occurring or syntheticallyproduced, either with natural abundance or in an isotopically enrichedform. For example, a reference to hydrogen includes within its scope ¹H,²H (D), and ³H (T). Similarly, references to carbon and oxygen includewithin their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. Theisotopes may be radioactive or non-radioactive. Radiolabelled compoundsof formula (I) may comprise a radioactive isotope selected from thegroup of ³H, ¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and⁸²Br. Preferably, the radioactive isotope is selected from the group of³H, ¹¹C and ¹⁸F.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

One skilled in the art will recognize that the compounds of formula (I),formula (II) and formula (III) each contain an optionally substitutedpyridin-2-one group, which group may tautomerize as shown below

One skilled in the art will further recognize that said group (and assuch the corresponding compounds of formula (I), formula (II) andformula (III)) may exist as either of its tautomeric forms, or as anymixture of its tautomeric forms.

Abbreviations used in the specification, particularly the Schemes andExamples, are as listed in Table A, below.

TABLE A Abbreviations AcOH = Acetic acid ANOVA = Analysis of Varianceaq. = Aqueous BAST = Bis(2-methoxyethyl)aminosulfur trifluoride solution50% w/w in toluene BINAP = 2,2′-Bis(diphenylphosphino)-1,1′-BinaphthylBoc₂O or BOC₂O = Boc Anhydride (di-tert-Butyl dicarbonate) BSA = BovineSerum Albumin BTEAC = Benzyl Triethyl Ammonium Chloride (BuO)₄Sn =Tetrabutoxystannane cAMP = Cyclic Adenosine MonoPhosphate DABCO =1,4-Diazabicyclo[2.2.2]octane DAST = Diethylaminosulfur trifluoride DBU= 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE = 1,2-Dichloroethane DCM =Dichloromethane Dess Martin = 1,1,1-Triacetoxy-1,1-dihydro-1,2-Periodinone or DMP benziodoxol-3(1H)-one DIAD =Diisopropylazodicarboxylate DIBAL = Diisobutylammonium hydride DIPEA orDIEA = Diisopropylethylamine DMA = Dimethyl Acetamide DMAP =4-N,N-Dimethylaminopyridine DME = Dimethoxy Ethane DMF =N,N-Dimethylformamide DMP = Dess Martin Periodinone DMSO =Dimethylsulfoxide dppf = 1,1′-Bis(diphenylphosphino)ferrocene EDCl =1-Ethyl-3-(3- dimethylaminopropyl)carbodiimide EDTA = Ethylene DiamineTetraacetic Acid eq. or equiv. = Equivalents (molar) ESI = Electrosprayionization EtBr = Ethyl Bromide EtOAc or EA = Ethyl acetate EtOH =Ethanol EtONa or NaOEt = Sodium Ethoxide EtOMs = Ethyl mesylate Et₃N orTEA = Triethylamine Et₃SiH Triethylsilane EtSO₂Cl = EthanesulfonylChloride FSK = Forskolin GSIS = Glucose Stimulated Insulin SecretionHATU = O-(7-Azabenzotriazol-1-yl)-N,N,N″,N″- Tetramethyl UroniumHexafluorophosphate HBSS = Hank′s Buffered Salt Solution HEPES =4-(2-Hydroxyethyl)-1-Piperizine Ethane Sulfonic Acid HMDS =Hexamethyldisilazane HPBCD = Hydroxypropyl-Beta-CycloDextrin HPLC = HighPressure Liquid Chromatography IFG = Impaired Fasting Glucose IGT =Impaired Glucose Tolerance IPA = Isopropanol i-Prl = Isopropyl Iodidei-Pr—NH₂ = Isoporpylamine I-PrSO₂Cl₂ = Isopropylsulfonyl Chloride KHMDS= Potassium bis(trimethylsilyl)amide KOAc = Potassium Acetate LAH =Lithium Aluminum Hydride Lawesson′s Reagent =2,4-Bis(4-methoxyphenyl)-1,3,2,4- dithiadiphosphetane-2,4-dithione LCMS= Liquid Chromatography/Mass Spectroscopy LDA = Lithium DiisopropylAmide LiHMDS = Lithium bis(trimethylsilyi)amide mCPBA =meta-Chloroperoxybenzoic acid MeCN = Acetonitrile MeI = Methyl IodideMeOH = Methanol MeOTs = Methyl tosylate Me₂SO₄ = Dimethyl Sulfate Mesylor Ms = Methylsulfonyl MS = Mass Spectroscopy MsCl = Mesyl Chloride(i.e. CH₃—SO₂—Cl) MsOH = Methanesulfonic Acid Mesylate = Methanesulfonate (i.e. —O—SO₂—CH₃) MOM = Methoxymethyl acetal (protectinggroup) MTBE = Methyl tert-Butyl Ether NAFLD = non-alcoholic fatty liverdisease NaBH(OAc)₃ or STAB = Sodium triacetoxyborohydride NaHMDS =Sodium bis(trimethylsilyl)amide NaOEt = Sodium Ethoxide NaOMe = SodiumMethoxide NASH = non-alcoholic steatohepatitis (NASH), NBS =N-Bromosuccinimide n-BuLi = n-Butyl Lithium NCS = N-ChlorosuccinimideNH₄OAc = Ammonium Acetate NMP = N-methyl-2-pyrrolidinone NMR = NuclearMagnetic Resonance Oxone = Potassium peroxymonosulfate PCC = Pyridiniumchlorochromate Pd—C = Palladium on Carbon Catalyst Pd(OAc)₂ =Palladium(II)acetate Pd(dppf)Cl₂ = [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh₃)₄ = Tetrakistriphenylphosphinepalladium (0) PE = Petroleum Ether Ph = Phenyl P(o-tol)₃ or (o-tol)₃P =Tri(ortho-tolyl) Phosphine PPA = Phenylpropanolamine PPh₃ = TriphenylPhosphine Py = Pyridine PyBrop = Bromotripyrrolidinophosphoniumhexafluorophosphate SELECTFLUOR ® = 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) SPA = ScintillationProximity Assay RT or rt = Room temperature SPA = ScintillationProximity Assay TBAB = Tetra-n-butylammonium bromide t-BOC or Boc =tert-Butocarbonyl t-BuLi = tert-Butyl Lithium t-BuOH = tert-Butanolt-BuOK = Potassium tert-butoxide t-BuOLi = Lithium tert-butoxide t-BuONa= Sodium tert-butoxide TEA = Triethylamine Tf = Trifyl (i.e. —SO₂—CF₃)TFA = Trifluoroacetic Acid TFAA = Trifluoroacetic anhydride Tf₂O =Triflic Anhydride (Trifluoromethanesulfonic anhydride) THF =Tetrahydrofuran THP = Tetrahydropyran TLC = Thin Layer ChromatographyTMS = Trimethylsilyl TMSCl = Trimethylsilyl Chloride TMSCN =Trimethylsilyl Cyanide TMSI = Trimethylsilyl Iodide TMSN₃ =Trimethylsilyl Azide TMSOTf = Trimethylsilyl Trifluoromethane SulfonateTosyl or Ts = para-Toluenesulfonyl Tosylate = para-Toluene sulfonate(i.e. —O—SO₂-(p- toluene) Triflate or OTf = Trifluoromethane sulfonateTsCl = para-Toluenesulfonic Chloride (i.e. (p- toluene)-SO₂—Cl) TsOH orpTSA = para-Toluenesulfonic Acid

As used herein, unless otherwise noted, the term “isolated form” shallmean that the compound of formula (I), compound of formula (II) orcompound of formula (III) is present in a form which is separate fromany solid mixture with another compound(s), solvent system or biologicalenvironment. In an embodiment of the present invention, the compound offormula (I), compound of formula (II) or compound of formula (III) ispresent in an isolated form.

As used herein, unless otherwise noted, the term “substantially pureform” shall mean that the mole percent of impurities in the isolatedcompound of formula (I), compound of formula (II) or compound of formula(III) is less than about 5 mole percent, preferably less than about 2mole percent, more preferably, less than about 0.5 mole percent, mostpreferably, less than about 0.1 mole percent. In an embodiment of thepresent invention, the compound of formula (I), compound of formula (II)or compound of formula (III) is present as a substantially pure form.

As used herein, unless otherwise noted, the term “substantially free ofa corresponding salt form(s)” when used to described the compound offormula (I), compound of formula (II) or compound of formula (III) shallmean that mole percent of the corresponding salt form(s) in the isolatedbase of formula (I), compound of formula (II) or compound of formula(III) is less than about 5 mole percent, preferably less than about 2mole percent, more preferably, less than about 0.5 mole percent, mostpreferably less than about 0.1 mole percent. In an embodiment of thepresent invention, the compound of formula (I), compound of formula (II)or compound of formula (III) is present in a form which is substantiallyfree of corresponding salt form(s).

As used herein, unless otherwise noted, the terms “treating”,“treatment” and the like, shall include the management and care of asubject or patient (preferably mammal, more preferably human) for thepurpose of combating a disease, condition, or disorder and includes theadministration of a compound of the present invention to prevent theonset of the symptoms or complications, alleviate the symptoms orcomplications, or eliminate the disease, condition, or disorder.

As used herein, unless otherwise noted, the term “prevention” shallinclude (a) reduction in the frequency of one or more symptoms; (b)reduction in the severity of one or more symptoms; (c) the delay oravoidance of the development of additional symptoms; and/or (d) delay oravoidance of the development of the disorder or condition.

One skilled in the art will recognize that wherein the present inventionis directed to methods of prevention, a subject in need of thereof (i.e.a subject in need of prevention) shall include any subject or patient(preferably a mammal, more preferably a human) who has experienced orexhibited at least one symptom of the disorder, disease or condition tobe prevented. Further, a subject in need thereof may additionally be asubject (preferably a mammal, more preferably a human) who has notexhibited any symptoms of the disorder, disease or condition to beprevented, but who has been deemed by a physician, clinician or othermedical profession to be at risk of developing said disorder, disease orcondition. For example, the subject may be deemed at risk of developinga disorder, disease or condition (and therefore in need of prevention orpreventive treatment) as a consequence of the subject's medical history,including, but not limited to, family history, pre-disposition,co-existing (comorbid) disorders or conditions, genetic testing, and thelike.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment. Preferably, the subject has experiencedand/or exhibited at least one symptom of the disease or disorder to betreated and/or prevented.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

As more extensively provided in this written description, terms such as“reacting” and “reacted” are used herein in reference to a chemicalentity that is any one of: (a) the actually recited form of suchchemical entity, and (b) any of the forms of such chemical entity in themedium in which the compound is being considered when named.

One skilled in the art will recognize that, where not otherwisespecified, the reaction step(s) is performed under suitable conditions,according to known methods, to provide the desired product. One skilledin the art will further recognize that, in the specification and claimsas presented herein, wherein a reagent or reagent class/type (e.g. base,solvent, etc.) is recited in more than one step of a process, theindividual reagents are independently selected for each reaction stepand may be the same of different from each other. For example whereintwo steps of a process recite an organic or inorganic base as a reagent,the organic or inorganic base selected for the first step may be thesame or different than the organic or inorganic base of the second step.

Further, one skilled in the art will recognize that wherein a reactionstep of the present invention may be carried out in a variety ofsolvents or solvent systems, said reaction step may also be carried outin a mixture of the suitable solvents or solvent systems. One skilled inthe art will further recognize that wherein two consecutive reaction orprocess steps are run without isolation of the intermediate product(i.e. the product of the first of the two consecutive reaction orprocess steps), then the first and second reaction or process steps maybe run in the same solvent or solvent system; or alternatively may berun in different solvents or solvent systems following solvent exchange,which may be completed according to known methods.

One skilled in the art will further recognize that the reaction orprocess step(s) as herein described (or claimed) are allowed to proceedfor a sufficient period of time until the reaction is complete, asdetermined by any method known to one skilled in the art, for example,chromatography (e.g. HPLC). In this context a “completed reaction orprocess step” shall mean that the reaction mixture contains asignificantly diminished amount of the starting material(s)/reagent(s)and a significantly reduced amount of the desired product(s), ascompared to the amounts of each present at the beginning of thereaction.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

To provide a more concise description, some of the quantitativeexpressions herein are recited as a range from about amount X to aboutamount Y. It is understood that wherein a range is recited, the range isnot limited to the recited upper and lower bounds, but rather includesthe full range from about amount X through about amount Y, or any amountor range therein.

Examples of suitable solvents, bases, reaction temperatures, and otherreaction parameters and components are provided in the detaileddescription which follows herein. One skilled in the art will recognizethat the listing of said examples is not intended, and should not beconstrued, as limiting in any way the invention set forth in the claimswhich follow thereafter.

As used herein, unless otherwise noted, the term “aprotic solvent” shallmean any solvent that does not yield a proton. Suitable examplesinclude, but are not limited to DMF, 1,4-dioxane, THF, acetonitrile,pyridine, 1,1-dichloroethane, dichloromethane, MTBE, toluene, acetone,and the like.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, and the like.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

As used herein, unless otherwise noted, the term “oxygen protectinggroup” shall mean a group which may be attached to an oxygen atom toprotect said oxygen atom from participating in a reaction and which maybe readily removed following the reaction. Suitable oxygen protectinggroups include, but are not limited to, acetyl, benzoyl,t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like.Other suitable oxygen protecting groups may be found in texts such as T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography.

The compounds may be prepared in racemic form, or individual enantiomersmay be prepared either by enantiospecific synthesis or by resolution.The compounds may, for example, be resolved into their componentenantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation with an optically active acid,such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

Additionally, chiral HPLC against a standard may be used to determinepercent enantiomeric excess (% ee). The enantiomeric excess may becalculated as follows[(Rmoles−Smoles)/(Rmoles+Smoles)]×100%

where Rmoles and Smoles are the R and S mole fractions in the mixturesuch that Rmoles+Smoles=1. The enantiomeric excess may alternatively becalculated from the specific rotations of the desired enantiomer and theprepared mixture as follows:ee=([α-obs]/[α-max])×100.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts include,but are not limited to, the following: acetate, benzenesulfonate,benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calciumedetate, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: acids including acetic acid, 2,2-dichloroacetic acid,acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid,hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lacticacid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotincacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid,4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid,sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,p-toluenesulfonic acid and undecylenic acid.

Representative bases which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: bases including ammonia, L-arginine, benethamine, benzathine,calcium hydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

Synthesis Schemes

Compounds of formula (I) wherein X is selected from the group consistingof —CR^(A)R^(B)—, —CR^(A)═, —CR^(A)R^(B)—CH₂—, —CH₂—CHR^(C)—, and—CR^(A)R^(B)—CR^(C)═ may be prepared from intermediate compounds offormula (a-16)

-   -   and/or compounds of formula (a-20)

wherein X^(a)═O is —CR^(A)═O, CR^(A)R^(B)—CH═O, —CH₂—CR^(C)═O or—CR^(A)R^(B)—CR^(C)═O, and which intermediate compounds may be asdescribed below.

Certain intermediate compounds, useful in the synthesis of compounds offormula (I) of the present invention may be prepared as described inScheme A-1, below.

Accordingly, a suitably substituted compound of formula (a-1), whereinLG¹ is a suitably selected leaving groups such as Br, Cl, OTf, and thelike, and wherein A^(Q) is an alkyl substituent such as methyl, ethyl,and the like, preferably methyl, a known compound or compound preparedby known methods, is reacted with a suitably substituted compound offormula (a-2), wherein the two R groups are the same and are selectedfrom the group consisting of OH and OPG⁰, wherein PG⁰ is a suitablyselected oxygen protecting group such as methyl, ethyl, isopropyl, andthe like, or the two R groups are taken together with the boron atom towhich they are bound to form

a known compound or compound prepared by known methods; in the presenceof a suitably selected catalyst such as Pd(OAc)₂, PdCl₂, Pd(PPh₃)₄, andthe like; in the presence of a suitably selected ligand such as PPh₃,dppf, BINAP, and the like; in the presence of a suitably selected basesuch as Na₂CO₃, K₃PO₄, t-BuOK, and the like; in a suitably selectedorganic solvent or mixture of organic solvent and water, such as THF,1,4-dioxane, a mixture of toluene and water, and the like; at atemperature in the range of form about 60° C. to about 120° C.; to yieldthe corresponding compound of formula (a-3).

The compound of formula (a-3) is reacted with a suitably selectedorganometallic reagent such as t-BuLi, LDA, LiHMDS, and the like; in asuitably selected organic solvent such as diethyl ether, THF,1,4-dioxane, and the like; at a temperature in the range of from about−78° C. to about 0° C.; and then immediately reacted with a suitablysubstituted compound of formula (a-4), a known compound or compoundprepared by known methods; to yield the corresponding compound offormula (a-5).

Certain intermediate compounds, useful in the synthesis of compounds offormula (I) of the present invention may be prepared as described inScheme A-2, below.

Accordingly, a suitably substituted compound of formula (a-3), preparedfor example as described in Scheme A-1 above, is reacted with a suitablyselected organometallic reagent such as t-BuLi, LDA, LiHMDS, and thelike; in a suitably selected organic solvent such as diethyl ether, THF,1,4-dioixane, and the like; at a temperature in the range of from about−78° C. to about 0° C.; and them immediately reacted with diethyloxalate, a known compound; to yield the corresponding compound offormula (a-6).

The compound of formula (a-6) is reacted with a suitably selectedreducing agent such as Et₃SiH, NaBH₄, NaBH₃(CN), and the like; in thepresence of a suitably selected acid such as TFA, AcOH, HCl, and thelike; in a suitably selected organic solvent such as DCM, diethyl ether,THF, and the like; at a temperature in the range of from about 0° C. toabout 25° C.; to yield the corresponding compound of formula (a-7).

The compound of formula (a-7) is optionally reacted with a suitablyselected base such as LDA, LiHMDS, KHMDS, and the like; in a suitablyselected organic solvent such as diethyl ether, THF, 1,4-dioxane, andthe like; at a temperature in the range of from about −78° C. to about0° C.; and then immediate reacted with a suitably substituted reagent,for example, a suitably substituted alkyl halide, alkyl triflate, alkyltosylate or alkyl mesylate; to yield the corresponding compound offormula (a-9).

One skilled in the art will recognize that wherein R^(A) and R^(B) arethe same the compound of formula (a-7) is reacted with a suitablyselected base such as LDA, HMDS, LiHMDS, NaHMDS, t-BuONa, t-BuOLi, andthe like; wherein the base is preferably present in an amount of about2.0 eq.; and then reacted with a suitably selected alkylating reagentsuch as CH₃I, EtBr, EtOMs, MeOTs, and the like; wherein the alkyl of thealkylating reagent corresponds to the desired R^(A)/R^(B) groups andwherein the alkylating reagent is preferably present in an amount of atleast about 2.0 eq.; to yield the corresponding compound of formula(a-9).

Alternatively, wherein R^(A) and R^(B) are different the compound offormula (a-7) is reacted with a suitably selected base such as LDA,KHMDS, LiHMDS, NaHMDS, t-BuONa, t-BuOLi, and the like; wherein the baseis preferably present in an amount of about 1.0 eq.; and then reactedwith a suitably selected alkylating reagent such as CH₃I, EtBr, EtOMs,MeOTs, and the like; wherein the alkyl corresponds to the desired R^(A)group; and wherein the alkylating reagent is preferably present in anamount of about 1.0 eq.; and then reacted with a second suitablyselected alkylating reagent wherein the alkyl corresponds to the desiredR^(B) group; and wherein the alkylating reagent is preferably present inan amount of about 1.0 eq.; to yield the corresponding compound offormula (a-9).

Alternatively, wherein R^(A) and R^(B) are taken together with thecarbon atom to which they are bound to form C₃₋₆cycloalkyl of formula(a-7) is reacted with a suitably selected base such as LDA, KHMDS,LiHMDS, NaHMDS, t-BuONa, t-BuOK, and the like; wherein the base ispreferably present in an amount of about 2.0 eq.; and then reacted witha suitably selected bis-alkylating reagent such as 1,2-di-Br-ethane,1-chloro-3-iodo-propane, 1-chloro-4-iodo-butane, and the like; whereinthe bis-alkyl of the alkylating reagent corresponds to the desiredR^(A)/R^(B) groups; and wherein the bis-alkylating reagent is preferablypresent in an amount of about 1.0 eq.; to yield the correspondingcompound of formula (a-9).

The compound of formula (a-9) is reacted with a suitably selected basesuch as DIBAL, LAH, LiBH₄, and the like; in a suitably selected organicsolvent such as DCM, diethyl ether, THF, and the like; at a temperaturein the range of from about −78° C. to about 0° C.; to yield thecorresponding compound of formula (a-10).

The compound of formula (a-10) is reacted with a suitably selectedoxidizing agent such as oxyl chloride/DMSO (Swern reagent), PCC,Dess-Martin reagent, and the like; in a suitably selected organicsolvent such as DCM, diethyl ether, THF, and the like; at a temperaturein the range of rom about 0° C. to about 25° C.; to yield thecorresponding compound of formula (a-11).

One skilled in the art will recognize that wherein the desired R^(A) andR^(B) are each hydrogen, the compound of formula (a-7) may besubstituted for the compound of (a-9) and reacted as described, to yieldthe corresponding compound of formula (a-11), wherein R^(A) and R^(B)are each hydrogen.

The compound of formula (a-11) may be further, optionally reacted with asuitably substituted organometallic reagent such as R^(C)—Li,R^(C)—MgBr, Zn(R^(C))₂, and the like, a known compound or compoundprepared by known methods; in a suitably selected organic solvent suchas DCM, diethyl ether, THF, and the like; at a temperature in the rangeof from about −78° C. to about 0° C.; to yield the correspondingcompound of formula (a-12).

The compound of formula (a-11) (when preparing compounds of formula (I)wherein the desired R^(C) group is hydrogen) or the compound of formula(a-12) (when preparing compounds of formula (I) wherein the desiredR^(C) group is other than hydrogen), is reacted with a suitably selectedoxidizing agent such as oxyl chloride/DMSO (Swern reagent), PCC,Dess-Martin reagent, and the like; in a suitably selected organicsolvent such as DCM, diethyl ether, THF, and the like; at a temperaturein the range of rom about 0° C. to about 25° C.; to yield thecorresponding compound of formula (a-13).

The compound of formula (a-13) is reacted with (methoxymethyl)phenylphosphonium chloride, a known compound; in the presence of a suitablyselected base such as LiHMDS, LDA, NaHMDS, and the like; in an organicsolvent such as THF, diethyl ether, 1,4-dioxane, and the like; at atemperature in the range of form about −78° C. to about 25° C.; to yieldthe corresponding compound of formula (a-14).

The compound of formula (a-14) is reacted with a suitably selected acidsuch as 1N HCl, 1N H₂SO₄, 48% HBr, and the like; in a suitably selectedorganic solvent such as acetonitrile, THF, 1,4-dioxane, and the like; ata temperature in the range of from about 0° C. to about 25° C.; to yieldthe corresponding compound of formula (a-15).

A suitably substituted compound of formula (a-6) may alternatively, bereacted with a suitably selected fluorinating reagent such as DAST,BAST, SELECTFLUOR®, and the like; in a suitably selected organic solventsuch as DCM, 1,2-di-Cl-ethane, chloroform, and the like; at atemperature in the range of from about −78° C. to about 0° C.; to yieldthe corresponding compound of formula (a-9), wherein R^(A) and R^(B) areeach fluoro. Said compound is then further reacted as described inScheme A-2 above, to yield the corresponding compounds of formula (a-11)and formula (a-15) wherein R^(A) and R^(B) are each fluoro.

A a suitably substituted compound of formula (a-3) may alternatively bereacted with a suitably selected organometallic reagent such as t-BuLi,LDA, LiHMDS, and the like; in a suitably selected organic solvent suchas diethyl ether, THF, 1,4-dioxane, and the like; at a temperature inthe range of from about −78° C. to about 0° C.; and them immediatelyreacted with ethyl glyoxalate, a known compound; to yield thecorresponding compound of formula (a-8)

The compound of formula (a-8) is then reacted a suitably selectedfluorinating reagent such as DAST, BAST, SELECTFLUOR®, and the like; ina suitably selected organic solvent such as DCM, 1,2-di-Cl-ethane,chloroform, and the like; at a temperature in the range of from about−78° C. to about 0° C.; to yield the corresponding compound of formula(a-9), R^(A) is hydrogen and R^(B) is fluoro. Said compound is thenfurther reacted as described in Scheme A-2 above, to yield thecorresponding compounds of formula (a-11) and formula (a-15) whereinR^(A) is hydrogen and R^(B) is fluoro.

Certain compounds of formula (I) may be prepared from the correspondingcompound of formula (a-16) as described in Scheme A-4, below.

Accordingly, a suitably substituted compound of formula (a-16) whereinX^(a) is selected from the group consisting of —CR^(A)—,—CR^(A)R^(B)—CH—, —CH₂—CR^(C)— or CR^(A)R^(B)—CR^(C)—, is reacted with asuitably substituted compound of formula (a-17), a known compound orcompound prepared by known methods; in the presence of a suitablyselected organometallic agent such as t-BuLi, LDA, LiHMDS, and the like;optionally in the presence of a suitably selected additive such as LiCl,and the like; in a suitably selected organic solvent such as THF,1.4-dioxane, diethyl ether, and the like; at a temperature in the rangeof from about −78° C. to about −10° C.; to yield the correspondingcompound of formula (a-18).

The compound of formula (a-18) is reacted with a suitably selectedacylating agent such as SOCl₂, oxyl chloride, MsCl, and the like; in thepresence of a suitably selected base such as TEA, pyridine, DIPEA, andthe like; in a suitably selected organic solvent such as DCM, THF,toluene, and the like; at a temperature in the range of from about 0° C.to about 25° C.; to yield the corresponding compound of formula (a-19).

The compound of formula (a-19) is reacted with a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected organic solvent such as acetonitrile, THF, 1,4-dioxane, and thelike; at a temperature in the range of from about 25° C. to about 100°C.; to yield the corresponding compound of formula (Ia).

The compound of formula (Ia) is further, optionally reacted with asuitably selected reducing agent such as hydrogen gas, for examplehydrogen gas under about 40-55 psi; in the presence of a suitablyselected catalyst such as 5-10% Pd on carbon, PtO₂, Ni, and the like; ina suitably selected organic solvent such as methanol, THF, ethylacetate, and the like; at a temperature in the range of from about 25°C. to about 60° C.; to yield the corresponding compound of formula (Ib).

Certain compounds of formula (I) wherein

is an optionally substituted imidazol-2-yl, may be prepared as describedin Scheme 5, below.

Accordingly, a suitably substituted compound of formula (a-20) whereinXa is selected from the group consisting of —CR^(A)R^(B)—,—CR^(A)R^(B)—CH₂— and —CH₂—CR^(C)— is reacted with a suitablysubstituted compound of formula (a-21), wherein each R representhydrogen or the desired imidazol-2-yl substituent (if present), an aknown compound or compound prepared by known methods; in the presence ofa suitably selected source of ammonium such as 7N NH₃/methanol, ammoniumacetate, ammonium hydroxide, and the like; in a suitably selectedorganic solvent such as methanol, ethanol, isopropanol, and the like; ata temperature in the range of form about 25° C. to about 70° C.; toyield the corresponding compound of formula (a-22).

The compound of formula (a-22) is reacted with a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected organic solvent such as acetonitrile, THF, 1,4-dioxane, and thelike; at a temperature in the range of from about 25° C. to about 100°C.; to yield the corresponding compound of formula (Ic).

Certain compounds of formula (I) may be prepared as described in SchemeA-6 below.

Accordingly, a suitably substituted compound of formula (a-20) whereinX^(a) is selected from the group consisting of —CH—, —CR^(A)—,—CR^(A)R^(B)—CH—, —CH₂—CR^(C)— and CR^(A)R^(B)—CR^(C)—, is reacted withtoluenesulfonylmethyl isocyanide (also known as tosMIC), a knowncompound; in the presence of a suitably selected base such as t-BuOK,NaOCH₂CH₃, NaH, and the like; in a suitably selected organic solventsuch as THF, 1,4-dioxane, DME, and the like; at a temperature in therange of form about −78° C. to about 0° C.; to yield the correspondingcompound of formula (a-23).

The compound of formula (a-23) is reacted with a suitably selected acidsuch as PPA, 4N HCl, 1N H₂SO₄, and the like; in a suitably selectedorganic solvent such as THF, 1,4-dioxane, DME, and the like; at atemperature in the range of from about 25° C. to about 80° C.; to yieldthe corresponding compound of formula (a-24).

Alternatively, a suitably substituted compound of formula (a-23) reactedwith a suitably selected base such as LDA, LiHMDS, KHMDS, and the like;in wherein X^(a) is —CH₂— is a suitably selected organic solvent such asdiethyl ether, THF, 1,4-dioxane, and the like; at a temperature in therange of from about −780° C. to about 0° C.; and then immediate reactedwith a suitably substituted alkylating reagent, for example, a suitablysubstituted C₁₋₆alkyl halide, C₁₋₆alkyl-OTf, C₁₋₆alkyl-OTs,C₁₋₆alkyl-OMs, and the like; wherein the reagent is preferably presentin an amount of at least about 2 molar equivalents; to yield thecorresponding compound of formula (a-23) wherein X^(a) is —CR^(A)R^(B)—and wherein R^(A) and R^(B) are each the same and are the correspondingC₁₋₆alkyl.

One skilled in the art will recognize that the compound of formula(a-23) wherein X^(a) is —CH₂— may alternatively be reacted with asuitably substituted R^(A)-substituted reagent or a suitably substitutedR^(B)-substituted reagent or reacted sequentially with both a suitablysubstituted R^(A)-substituted reagent and then with a suitablysubstituted R^(B)-substituted reagent (wherein the substituted reagentis for example with a suitably substituted halide, triflate, tosylate,mesylate, and the like) or a suitably substituted R^(A)R^(B) substitutedreagent (wherein the suitably substituted reagent is, for example, asuitably substituted di-halide, di-mesylate, di-tosylate, and the like)according to known methods, to yield the corresponding compound offormula (a-23), wherein the desired R^(A) and/or R^(B) substituentgroups are incorporated into the compound structure.

The compound of formula (a-24) is reacted with hydrazine, a knowncompound; in the presence of a suitably selected aldehyde equivalentsuch as DMF-DMA, 1,2-dimethoxy-N,N-dimethylethan-1-amine,(OCH₃)₂—(R)C—N(CH₃)₂ (where R represents a desired substituent on thefinal compound of formula (I)), and the like; in a suitably selectedacidic solvent such as acetonitrile, TFA, aqueous formic acid solution,and the like; at a temperature in the range of from about 60° C. toabout 100° C.; to yield the corresponding compound of formula (a-25),wherein Z is ═C(R)—.

The compound of formula (a-25) is reacted with a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected organic solvent such as acetonitrile, THF, 1,4-dioxane, and thelike; at a temperature in the range of from about 25° C. to about 100°C.; to yield the corresponding compound of formula (Id).

Alternatively, the compound of formula (a-23) is reacted with a suitablyselected source of azide, such as NaN₃, TMSN₃, and the like; in thepresence of an organic or inorganic acid such as NH₄Cl, (BuO)₄Sn, andthe like; in a suitably selected organic solvent such as toluene, THF,1,4-dioxane, and the like; at a temperature in the range of from about60° C. to about 110° C.; to yield the corresponding compound of formula(a-25), wherein Z is ═N—.

The compound of formula (a-25) is then reacted as described above, toyield the corresponding compound of formula (Id).

One skilled in the art will recognize that the compound of formula(a-24) may alternatively be prepared from the corresponding compound offormula (a-26)

by reacting with a suitably selected source of ammonia such as 7NNH₃/methanol, ammonium acetate, ammonium hydroxide, and the like; in asuitably selected polar solvent such as water, methanol, ethanol, andthe like; at a temperature in the range of form about 50° C. to about100° C.

Alternatively, a suitably substituted compound of formula (a-23) orformula (a-27) or formula (a-26) may be reacted with a suitably selectedbase such as KOH, NaOH, Ba(OH)₂, and the like; in a suitably selectedorganic solvent such as THF, methanol, ethanol, and the like; at atemperature in the range of from about 80° C. to about 120° C.; to yieldthe corresponding compound of formula (a-28)

wherein the cyano or ester group is converted to the corresponding acidgroup; the compound of formula (a-28) is then reacted with a suitablysubstituted amine; in the presence of a suitably selected coupling agentsuch as HATU, EDCl, PyBrop, and the like; in the presence of a suitablyselected base such as TEA, DIPEA, DBU, and the like; in a suitablyselected organic solvent such as DCM, THF, DMF, and the like; at atemperature in the range of from about 25° C. to about 50° C.; to yieldthe corresponding compound wherein the acid group is converted to thecorresponding amide; and said intermediate is then reacted as describedabove to (by reacting with a suitably selected acid such as pyridinehydrochloride, TMSI, TsOH, and the like; in a suitably selected organicsolvent such as acetonitrile, THF, 1,4-dioxane, and the like; at atemperature in the range of from about 25° C. to about 100° C.; to yieldthe corresponding compound of formula (I) wherein X is selected from thegroup consisting of —CH—, —CR^(A)—, —CR^(A)R^(B)—CH—, —CH₂—CR^(C)— andCR^(A)R^(B)—CR^(C)—.

Certain compounds of formula (I) may be prepared as described in SchemeA-7 below.

Accordingly, a suitably substituted compound of formula (a-27) whereinXa is —CR^(A)R^(B)—, —CR^(A)R^(B)—CH₂—, CH₂—CR^(C)— or—CR^(A)R^(B)—CR^(C)—, is reacted with hydroxylamine, a known compound;in the presence of a suitably selected base such as t-BuOK, NaOEt,NaOMe, and the like; in a suitably selected organic solvent such asethanol, IPA, t-butanol, and the like; at a temperature in the range offrom about 60° C. to about 100° C.; to yield the corresponding compoundof formula (a-29).

The compound of formula (a-29) is reacted with CDI, a known compound; inthe presence of a suitably selected organic base such as DBU, DABCO,DIPEA, and the like; in a suitably selected organic solvent such as THF.DME, 1,4-dioxane, and the like; at a temperature in the range of fromabout 60° C. to about 100° C.; to yield the corresponding compound offormula (a-30).

The compound of formula (a-30) is reacted with a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected organic solvent such as acetonitrile, THF, 1,4-dioxane, and thelike; at a temperature in the range of from about 25° C. to about 100°C.; to yield the corresponding compound of formula (Ie).

Certain compounds of formula (I) may be prepared as described in SchemeA-8 below.

Accordingly, a suitably substituted compound of formula (a-27) whereinXa is —CR^(A)R^(B)—, —CR^(A)R^(B)—CH₂—, CH₂—CR^(C)— or—CR^(A)R^(B)—CR^(C)— is reacted with a halogenating agent such as SOCl₂,SOBr₂, and the like, or with oxalyl chloride, a known compound; in asuitably selected C₁₋₄alcohol of the formula Y—OH, such as ethanol,methanol, isopropanol, and the like; at a temperature in the range offrom about 0° C. to about 60° C.; to yield the corresponding compound offormula (a-31).

The compound of formula (a-31) is reacted with a suitably selected basesuch as LiOH, NaOH, KOH, and the like; in a suitably selected solvent ormixture of solvents such as THF, 1,4-dioxane, a mixture of methanol andwater, and the like; at a temperature in the range of form about 0° C.to about 60° C.; to yield the corresponding compound of formula (a-32).

The compound of formula (a-32) is reacted with hydrazine, a knowncompound; in the presence of a suitably selected coupling agent such asHATU, EDCl, PyBrop, and the like; in a suitably selected organic solventsuch as THF, 1,4-dioxane, DCM, and the like; at a temperature in therange of form about 0° C. to about 60° C.; to yield the correspondingcompound of formula (a-33).

The compound of formula (a-33) is reacted with a suitably substitutedorthoformate, a compound of formula (a-34), wherein R′ represents adesired substituent on the

in the presence of a suitably selected catalyst such as NH₄Cl, CH₃I,NaCl, and the like; in a suitably selected organic solvent such asacetonitrile, ethanol, isopropanol, and the like; at a temperature inthe range of from about 60° C. to about 100° C.; to yield thecorresponding compound of formula (a-35).

The compound of formula (a-35) is reacted with a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected organic solvent such as acetonitrile, THF, 1,4-dioxane, and thelike; at a temperature in the range of from about 25° C. to about 100°C.; to yield the corresponding compound of formula (If).

Certain compounds of formula (I) may be prepared as described in SchemeA-9, below.

Accordingly, a suitably substituted compound of formula (a-20) whereinX^(a) is selected from the group consisting of —CHR^(A)—, —CR^(A)R^(B)—,—CR^(A)R^(B)—CH₂—, CH₂—CR^(C)— or —CR^(A)R^(B)—CR^(C) is reacted with asuitably substituted hydrazine or thiohydrazine, a compound of formula(a-36), wherein Z is O or S, respectively, and wherein R″ represents adesired substituent on the

a known compound or compound prepared by known methods; in the presenceof a suitably selected acid such as pTSA, MsOH, PPA, and the like; in asuitably selected organic solvent such as methanol, ethanol,isopropanol, and the like; at a temperature in the range of form about25° C. to about 85° C.; to yield the corresponding compound of formula(a-37).

The compound of formula (a-37) is reacted with I₂ or Br₂; in thepresence of a suitably selected base such as K₂CO₃, K₃PO₄, Na₂CO₃, andthe like; in an organic solvent such as THF, 1,4-dioxane, toluene, andthe like; at a temperature in the range of form about 60° C. to about100° C.; to yield the corresponding compound of formula (a-38).

The compound of formula (a-37) is reacted with a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected organic solvent such as acetonitrile, THF, 1,4-dioxane, and thelike; at a temperature in the range of from about 25° C. to about 100°C.; to yield the corresponding compound of formula (Ig).

One skilled in the art will recognize that additional compounds offormula (I) wherein

is a nitrogen containing heterocyclyl ring structure may be preparedfrom a suitably substituted compound of formula (a-20), a known compoundor compound prepared by known methods, or compound prepared according asdescribed herein (for example in the Schemes and/or Examples) byreacting said compound according to known ring closure/ring formationchemistry, for example as described in “Heterocyclic Chemistry” by J. A.JOULE, K. MILLS, Blackwell publishing; “Fundamentals of HeterocyclicChemistry: Importance in Nature and in the Synthesis of Pharmaceuticals”by L. D. QUIN, J. A. TYRELL, Wiley publishing; and then reacting theresulting compound to convert the —OA^(Q) group to the ═O group; toyield the corresponding compound of formula (I).

Certain compounds of formula (I) may be prepared as described in SchemeA-10, below.

Accordingly, a suitably substituted compound of formula (a-16), whereinX^(a) is selected from the group consisting of —CR^(A)═, CH₂—CR^(C)═,CR^(A)R^(B)—CH═, is reacted with a suitably substituted nitrogencontaining, optionally substituted

a compound of formula (a-39), a known compound or compound prepared byknown methods; in the presence of a suitably selected reducing agentsuch as NaBH₄, NaBH₃(CN), NaBH(OAc)₃, and the like; in a suitablyselected organic solvent such as DCM, THF, methanol, and the like; at atemperature in the range of from about 0° C. to about 25° C.; to yieldthe corresponding compound of formula (a-40).

The compound of formula (a-40) is reacted with a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected organic solvent such as acetonitrile, THF, 1,4-dioxane, and thelike; at a temperature in the range of from about 25° C. to about 100°C.; to yield the corresponding compound of formula (Ih).

Certain compounds of formula (I) may be prepared as described in SchemeA-11, below.

Accordingly, a suitably substituted compound of formula (a-16) whereinX^(a) is selected from the group consisting of —CR^(A)═, CH₂—CR^(C)═,CR^(A)R^(B)—CH═, is reacted with a suitably selected reducing agent suchas NaBH₄, NaBH₃(CN), NaBH(OAc)₃, and the like; in a suitably selectedorganic solvent such as DCM, THF, methanol, and the like; at atemperature in the range of from about 0° C. to about 25° C.; to yieldthe corresponding compound of formula (a-41).

The compound of formula (a-41) is reacted with a suitably selectedchlorinating agent such as mesyl chloride, tosyl chloride, PPh₃/CCl₄,and the like; in the presence of a suitably selected organic base suchas pyridine, TEA, DIPEA, and the like; in a suitably selected organicsolvent such as DCM, THF, diethyl ether, and the like; at a temperaturein the range of from about 0° C. to about 25° C.; to yield thecorresponding compound of formula (a-42).

The compound of formula (a-42) is reacted with a suitably substitutednitrogen containing aryl group, a compound of formula (a-43), a knowncompound or compound prepared by known methods; in the presence of asuitably selected base such as NaH, Cs₂CO₃, t-BuOK, and the like; in asuitably selected organic solvent such as THF, diethyl ether, DMF, andthe like; at a temperature in the range of from about 0° C. to about 80°C.; to yield the corresponding compound of formula (a-44).

The compound of formula (a-44) is reacted with a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected organic solvent such as acetonitrile, THF, 1,4-dioxane, and thelike; at a temperature in the range of from about 25° C. to about 100°C.; to yield the corresponding compound of formula (Ij).

Certain compound of formula (I) more particularly compounds of formula(I) wherein X is selected from the group consisting of—CR^(A)R^(B)—N(R^(D))— or —CR^(A)R^(B)—CH₂—N(R^(D))— may be prepared asdescribed in Scheme A-12, below.

Accordingly, a suitably substituted compound of formula (a-42), whereinX^(a) is selected from the group consisting of —CR^(A)R^(B)— and—CR^(A)R^(B)—CH₂— is reacted with a suitably substituted amine, acompound of formula (a-43), a known compound or compound prepared byknown methods; in the presence of a suitably inorganic base reagent suchas Cs₂CO₃, NaH, K₂CO₃, and the like; in a suitably selected organicsolvent such as DMF, THF, NMP, and the like; at a temperature in therange of from about 25° C. to about 100° C.; to yield the correspondingcompound of formula (a-44).

The compound of formula (a-44) is then reacted with a suitably selectedacid such as pyridine hydrochloride, TMSI, TsOH, and the like; in asuitably selected organic solvent such as acetonitrile, THF,1,4-dioxane, and the like; at a temperature in the range of from about25° C. to about 100° C.; to yield the corresponding compound of formula(Ik).

Certain compounds of formula (I), more particularly compounds of formula(I) wherein X is selected from the group consisting of—CR^(A)R^(B)—N(R^(D))—SO₂— or —CR^(A)R^(B)—CH₂—N(R^(D))—SO₂ may beprepared by as described in Scheme A-13 below.

Accordingly, a suitably substituted compound of formula (a-16) whereinX^(a) is selected from the group consisting of —CR^(A)R^(B)— and—CR^(A)R^(B)—CH₂— is reacted with a suitably substituted amine, acompound of formula (a-45), a known compound or compound prepared byknown methods; in the presence of a suitably reducing reagent such asNaBH₄, NaBH₃(CN), NaBH(OAc)₃, and the like; in a suitably selectedorganic solvent such as DCM, THF, methanol, and the like; at atemperature in the range of from about 0° C. to about 25° C.; to yieldthe corresponding compound of formula (a-46).

The compound of formula (a-46) is reacted with a suitably substitutedsulfonyl chloride reagent, a compound of formula (a-47), a knowncompound or compound prepared by known methods; in the presence of asuitably organic base such as TEA, DIPEA, pyridine, and the like; in asuitably selected organic solvent such as THF, DCM, 1,2-dicholorethane,and the like; at a temperature in the range of from about 0° C. to about40° C.; to yield the corresponding compound of formula (a-48).

The compound of formula (a-48) is reacted with a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected organic solvent such as acetonitrile, THF, 1,4-dioxane, and thelike; at a temperature in the range of from about 25° C. to about 100°C.; to yield the corresponding compound of formula (Im).

Certain compounds of formula (I), more particularly compounds of formula(I) wherein X is —CR^(A)R^(B)—CH₂—SO₂— may be prepared as described inScheme A-14, below.

Accordingly, a suitably substituted compound of formula (a-42) whereinX^(a) is —CR^(A)R^(B)—CH₂— is reacted with a suitably substitutedcompound of formula (a-49), a known compound or compound prepared byknown methods; in the presence of a suitably selected base such asK₂CO₃, NaH, Cs₂CO₃, and the like; in a suitably selected organic solventsuch as DMF, THF, NMP, and the like; at a temperature in the range offrom about 25° C. to about 80° C.; to yield the corresponding compoundof formula (a-50).

The compound of formula (a-50) is reacted with an oxidative reagent suchas mCPBA, OXONE, H₂O₂ and the like; in a suitably selected organicsolvent such as acetonitrile, DCM, 1,2-dicholorethane, and the like; ata temperature in the range of from about 0° C. to about 40° C.; to yieldthe corresponding compound of formula (a-51).

The compound of formula (a-51) is reacted with a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected organic solvent such as acetonitrile, THF, 1,4-dioxane, and thelike; at a temperature in the range of from about 25° C. to about 100°C.; to yield the corresponding compound of formula (In).

Certain compounds of formula (II), more particularly compounds offormula (II) wherein R⁵ is hydrogen, may be prepared as described inScheme B-1.

Accordingly, a suitably substituted compound of formula (b-1), whereinA^(Q) is a suitably selected alkyl such as methyl, ethyl, and the like,preferably methyl, a known compound or compound prepared by knownmethods, is reacted with a suitably selected base such as t-BuLi, LDA,LiHMDS, and the like; in a suitably selected organic solvent such asTHF, diethyl ether, 1,4-dioxane, and the like; at a temperature in therange of from about −78° C. to about 0° C.; followed by reaction with asuitably substituted compound of formula (b-2), a known compound orcompound prepared by known methods; to yield the corresponding compoundof formula (b-3).

The compound of formula (b-3) is reacted with a suitably selectedreducing agent such as Et₃SiH, NaBH₄, NaBH₃(CN), and the like; in thepresence of a suitably selected acid such as TFA, AcOH, HCl, and thelike; in a suitably selected organic solvent such as DCM, diethyl ether,THF, and the like; at a temperature in the range of from about 0° C. toabout 25° C.; to yield the corresponding compound of formula (b-4).

The compound of formula (b-4) is reacted with a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected organic solvent such as acetonitrile, THF, 1,4-dioxane, and thelike; to yield the corresponding compound of formula (IIa).

One skilled in the art will recognize that the compound of formula (b-3)may alternatively be reacted with a suitably selected fluorinating agentsuch as DAST, BAST, SELECTFLUOR®, and the like; in a suitably selectedorganic solvent such as DCM, 1,2-dichloroethane, THF, and the like; at atemperature in the range of from about −78° C. to about 0° C.; to yieldthe corresponding compound wherein the —OH group is converted to thecorresponding —F substituent. Said compound is then reacted with asuitably selected acid, as described above; to yield the correspondingcompound of formula (II), wherein R⁵ is fluoro.

Certain compounds of formula (II), more particularly compounds offormula (II) wherein

is 2-(NR^(F)R^(G) substituted)-4,5-dihydro-imidazol-5-yl and wherein R⁵is selected from the group consisting of hydrogen, C₁₋₄alkyl,C₃₋₆cycloalkyl and —C(O)NR^(U)R^(V) may alternatively be prepared asdescribe in Scheme B-2.

Accordingly, a suitably substituted compound of formula (b-5) whereinA^(Q) is a suitably selected alkyl such as methyl, ethyl, and the like,preferably methyl, a known compound or compound prepared by knownmethods is reacted with TMSCN, a known compound; in the presence of asuitably selected source of ammonia such as NH₄Cl, 7N NH₃/methanol,(NH₄)₂CO₃, and the like; in a suitably selected organic solvent such asMeOH, EtOH, IPA, and the like; at a temperature in the range of fromabout 25° C. to about 80° C.; to yield the corresponding compound offormula (b-6).

The compound of formula (b-6) is reacted with hydrogen gas (for exampleat 30-60 psi); in the presence of a suitably selected catalyst such as5-10% Pd/C, Pt₂O, Ni, and the like; in a suitably selected organicsolvent such as MeOH, THF, ethyl acetate, and the like; at a temperaturein the range of from about 25° C. to about 50° C.; to yield thecorresponding compound of formula (b-7).

The compound of formula (b-7) is reacted with a suitably selected sourceof thione such as CS₂, thioimidazole, and the like; in the presence of asuitably selected base such as TEA, DIPEA, DBU, and the like; in asuitably selected organic solvent such as DCM, THF, diethyl ether, andthe like; at a temperature in the range of from about 0° C. to about 50°C.; to yield the corresponding compound of formula (b-8).

The compound of formula (b-8) is reacted with a suitably selectedC₁₋₄alkylating agent (for example a methylating agent, an ethylatingagent, an isopropylating agent, and the like) such as CH₃I, Me₂SO₄,CH₃CH₂I, i-Prl, and the like; in the presence of a suitably selectedbase such as TEA, DIPEA, K₂CO₃, and the like; in a suitably selectedorganic solvent such as DCM, THF, DMF, and the like; at a temperature inthe range of from about 25° C. to about 80° C.; to yield thecorresponding compound of formula (b-9).

The compound of formula (b-9) is reacted with a suitably substitutedcompound of formula (b-10), a known compound or compound prepared byknown methods; in the presence of a suitably selected base such as NaH,Cs₃CO₃, t-BuOK, and the like; in a suitably selected organic solventsuch as THF, diethyl ether, DMF, and the like; at a temperature in therange of from about 25° C. to about 80° C.; to yield the correspondingcompound of formula (b-11).

The compound of formula (b-11) is reacted with a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected organic solvent such as acetonitrile, THF, 1,4-dioxane, and thelike; at a temperature in the range of from about 25° C. to about 100°C.; to yield the corresponding compound of formula (IIb).

Certain compounds of formula (II), more particularly compounds offormula (II) wherein

is 1H-imidazo[1,2-a]imidazol-2(3H)-one or5H-imidazo[2,1-c][1,2,4]triazol-6(7H)-one and wherein R⁵ is selectedfrom the group consisting of hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl and—C(O)NR^(U)R^(V); may alternatively be prepared as described in SchemeB-3.

Accordingly, a suitably substituted compound of formula (b-5), whereinA^(Q) is a suitably selected alkyl such as methyl, ethyl, and the like,preferably methyl, a known compound or compound prepared by knownmethods, is reacted with TMSCN, a known compound; in the presence of asuitably selected source of ammonia such as NH₄OH, (NH₄)₂CO₃, and thelike; in a suitably selected organic solvent such as MeOH, EtOH, IPA,and the like; at a temperature in the range of from about 60° C. toabout 100° C.; to yield the corresponding compound of formula (b-12).

The compound of formula (b-12) is reacted with a suitably selectedprotecting reagent, a known compound or compound prepared by knownmethods; in the presence of a suitably selected base such as NaH, K₂CO₃,TEA, and the like; in a suitably selected organic solvent such as DCM,THF, DMF, and the like; at a temperature in the range of from about 0°C. to about 50° C.; to yield the corresponding protected compound offormula (b-14), wherein PG¹ is the corresponding protecting group, suchas benzyl, p-methoxybenzyl (PMB), 3,4-dimethoxy-benzyl, and the like.

The compound of formula (b-14) is reacted with a suitably selectedsource of sulfur such as S, P₂S₅, Lawesson's reagent, and the like; in asuitably selected organic solvent such as toluene, THF, xylene, and thelike; at a temperature in the range of from about 60° C. to about 140°C.; to yield the corresponding compound of formula (b-15).

The compound of formula (b-15) is reacted with a suitably selectedsource of methyl such as MeI, Me₂SO₄, and the like; in the presence of asuitably selected base such as TEA, DIPEA, K₂CO₃, and the like; in asuitably selected organic solvent such as DCM, THF, DMF, and the like;at a temperature in the range of from about 25° C. to about 80° C.; toyield the corresponding compound of formula (b-16).

The compound of formula (b-16) is reacted with a suitably substitutedamine compound of formula (b-17), wherein W is selected from the groupconsisting of NH and CH₂, a known compound or compound prepared by knownmethods; in the presence of a suitably selected base such as NaH,Cs₂CO₃, t-BuOK, and the like; in a suitably selected organic solventsuch as THF, diethyl ether, DMF, and the like; at a temperature in therange of from about 25° C. to about 80° C.; to yield the correspondingcompound of formula (b-18).

The compound of formula (b-18) is reacted with a suitably selected acidsuch as H₂SO₄, PPA, pTSA, and the like; in a suitably selected organicsolvent such as toluene, THF, 1,4-dioxane, and the like; at atemperature in the range of from about 60° C. to about 120° C.; to yieldthe corresponding compound of formula (b-19).

The compound of formula (b-19) is reacted to remove the PG^(Y)protecting group, for example, reacted with hydrogen gas, at for example30-60 psi; in the presence of a suitably selected catalyst such as 5-10%Pd/C, PtO₂, Ni, and the like; in a suitably selected organic solventsuch as MeOH, THF, ethyl acetate, and the like; at a temperature in therange of from about 25° C. to about 50° C.; to yield the correspondingcompound of formula (b-20).

The compound of formula (b-20) is reacted with a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected organic solvent such as acetonitrile, THF, 1,4-dioxane, and thelike; at a temperature in the range of form about 25° C. to about 100°C.; to yield the corresponding compound of formula (IIc).

Additional compounds of formula (II) wherein R⁵ is selected from thegroup consisting of C₁₋₄alkyl, C₃₋₈cycloalkyl and —C(O)NR^(U)R^(V) maybe prepared as described in Scheme B-4, below.

Accordingly, a suitably substituted compound of formula (b-1), whereinA^(Q) is a suitably selected alkyl such as methyl, ethyl, and the like,preferably methyl, a known compound or compound prepared by knownmethods, is reacted with a suitably selected base such as t-BuLi, LDA,LiHMDS, and the like; in a suitably selected organic solvent such asTHF, diethyl ether, 1,4-dioxane, and the like; at a temperature in therange of from about −78° C. to about 0° C.; followed by reaction with asuitably substituted compound of formula (b-21), wherein R⁵ is selectedfrom the group consisting of C₁₋₄alkyl, C₃₋₈cycloalkyl and—C(O)NR^(U)R^(V), a known compound or compound prepared by knownmethods; to yield the corresponding compound of formula (b-22), whereinR⁵ is selected from the group consisting of C₁₋₄alkyl, C₃₋₈cycloalkyland —C(O)NR^(U)R^(V).

The compound of formula (b-22) is then substituted for the compound offormula (b-5) in Scheme B-2 or B-3 and reacted as described therein; toyield the corresponding compound of formula (IId).

One skilled in the art will recognize that additional compounds offormula (II) wherein

is a nitrogen containing heterocyclyl ring structure and wherein R⁵ isother than OH or fluoro, may be prepared from a suitably substitutedcompound of formula (b-5), a known compound or compound prepared byknown methods, or compound prepared according as described herein (forexample in the Schemes and/or Examples) by reacting said compoundaccording to known ring closure/ring formation chemistry, for example asdescribed in, for example, “Heterocyclic Chemistry” by J. A. JOULE, K.MILLS, Blackwell publishing; “Fundamentals of Heterocyclic Chemistry:Importance in Nature and in the Synthesis of Pharmaceuticals” by L. D.QUIN, J. A. TYRELL, Wiley publishing; “Advances in HeterocyclicChemistry” Volume 1-116, Elsevier publishing; “Modern HeterocyclicChemistry” Volume 1-4, by J. Alvarez-Builla, J. J, Vaquero, J.Barluenga, Wiley publishing; “Comprehensive Heterocyclic Chemistry”Volume 1-8, by C. W. Rees, A. R. Katritzky, Pergamon publishing; andthen reacting the resulting compound to convert the —OA^(Q) group to the═O group; to yield the corresponding compound of formula (I).

Compounds of formula (III) wherein Z is selected from the groupconsisting of —C(O)—NR^(L)R^(M), —C(O)—NH—OR^(N), —C(O)—NH—SO₂—R^(N);—C(O)—NH(CH(CH₂OH)₂), —C(O)NH(C(CH₂OH)₃), —C(O)—NH—(CH₂—CH₂O)_(a)—R^(N),—C(O)—NH—CH(CH₂O—(CH₂CH₂—O)_(b)—R^(N))₂,—C(O)—NH—C(CH₂O—(CH₂CH₂—O—)_(b)—R^(N))₃), —C(O)—NH—CH₂CH₂—NR^(P)R^(Q),and —C(O)—NH—(CH₂CH₂—O)_(a)—CH₂CH₂—NR^(P)R^(Q), may be prepared asdescribed in Scheme C-1, below.

Accordingly, a suitably substituted compound of formula (c-1), a knowncompound or compound prepared by known methods, is reacted with asuitably selected base such as KOH, NaOH, Ba(OH)₂, and the like; in asuitably selected organic solvent such as THF, methanol, ethanol, andthe like; at a temperature in the range of from about 80° C. to about120° C.; to yield the corresponding compound of formula (c-2).

The compound of formula (c-2) is reacted with a suitably substitutedamine compound of formula (c-3), wherein Q¹ and Q² are R^(L) and R^(M)or Q¹ is hydrogen and Q² is selected from the group consisting of—OR^(N), —SO₂—R^(N), —(CH₂—CH₂O)_(a)—R^(N),—CH(CH₂O—(CH₂CH₂—O)_(b)—R^(N))₂, —C(CH₂O—(CH₂CH₂—O—)_(b)—R^(N))₃),—CH₂CH₂—NR^(P)R^(Q) and —(CH₂CH₂—O)_(a)—CH₂CH₂—NR^(P)R^(Q), a knowncompound or compound prepared by known methods; in the presence of asuitably selected coupling agent such as HATU, EDCl, PyBrop, and thelike; in the presence of a suitably selected base such as TEA, DIPEA,DBU, and the like; in a suitably selected organic solvent such as DCM,THF, DMF, and the like; at a temperature in the range of from about 25°C. to about 50° C.; to yield the corresponding compound of formula(c-4).

The compound of formula (c-4) is reacted with a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected organic solvent such as acetonitrile, THF, 1,4-dioxane, and thelike; at a temperature in the range of from about 25° C. to about 100°C.; to yield the corresponding compound of formula (IIIa).

One skilled in the art will recognize that the processes described inSchemes C-1 may alternatively be used to make compounds of formula (I),more particularly compounds of formula (I) wherein

is a nitrogen bound, optionally substituted ring group, by substitutinga suitably substituted compound of formula (a-27)

for the compound of formula (c-1) and substituting the desired nitrogencontaining

for the compound of formula (c-3), and reacting the compounds asdescribed in Scheme C-1.

Compounds of formula (III) wherein Y^(a) is selected from the groupconsisting of —CR^(H)— and —CR^(H)R^(J)—CR^(K)— and wherein X isselected from the group consisting of —NR^(S)—C(O)—NR^(P)R^(Q) and—NR^(S)—C(O)—NH—CH₂CH₂—NR^(P)R^(Q) may be prepared as described inScheme C-2, below.

Accordingly, a suitably substituted compound of formula (c-5), whereinY^(a) is selected from the group consisting of —CR^(H)— and—CR^(H)R^(J)—CR^(K)—, a known compound or compound prepared by knownmethods, is reacted with a suitably substituted compound of formula(c-6), a known compound or compound prepared by known methods, in thepresence of a suitably selected reducing agent such as NaBH(OAc)₃,NaBH₃CN, NaBH₄, and the like; in a suitably selected organic solventsuch as DCM, THF, methanol, and the like; at a temperature in the rangeof from about 0° C. to about 60° C.; to yield the corresponding compoundof formula (c-7).

The compound of formula (c-7) is reacted with a suitably substitutedisocyanate of formula (c-8), a known compound or compound prepared byknown methods; in the presence of a suitably selected base such as TEA,DIPEA, pyridine, and the like; in a suitably selected organic solventsuch as DCM, THF, DMF, and the like; at a temperature in the range offrom about 25° C. to about 50° C.; to yield the corresponding compoundof formula (c-9).

The compound of formula (c-9) is reacted with. a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected solvent such as acetonitrile, THF, 1,4-dioxane, and the like;at a temperature in the range of from about 25° C. to about 100° C.; toyield the corresponding compound of formula (IIIb)

Compounds of formula (III) wherein Y is —CR^(H)R^(J)— and wherein X isselected from the group consisting of —NR^(S)—C(O)—NR^(P)R^(Q) and—NR^(S)—C(O)—NH—CH₂CH₂—NR^(P)R^(Q) may be prepared as described inScheme C-3, below.

Accordingly, a suitably substituted compound of formula (c-10), whereinY^(a) is —CR^(H)R^(J)—, a known compound or compound prepared by knownmethods (for example, according to the methods described for above forthe preparation of compounds of formula (a-28), substituting the desired—Y— substituent group for the —X^(a)— substituent group) is reacted witha suitably selected azide source such as DPPA, thionyl chloride/sodiumazide, and the like, in the presence of a suitably organic base such asTEA, DIPEA, tributylamine, and the like; in a suitably selected organicsolvent such as toluene, THF, 1,4-dioxane, and the like; at atemperature in the range of from about 80° C. to about 110° C.; to yieldthe corresponding compound of formula (c-11).

The compound of formula (c-11) is reacted with a suitably substitutedamine, a compound of the formula NR^(P)R^(Q)—H or a compound of theformula NH₂—CH₂CH₂—NR^(P)R^(Q), a known compound or compound prepared byknown methods; in the presence of a suitably selected base such as TEA,DIPEA, pyridine, and the like; in a suitably selected organic solventsuch as toluene, THF, 1,4-dioxane, and the like; at a temperature in therange of from about 25° C. to about 80° C.; to yield the correspondingcompound of formula (c-12), wherein Z^(a) is the corresponding—NR^(P)R^(Q) or —NH—CH₂CH₂—NR^(P)R^(Q) group, respectively.

The compound of formula (c-12) is reacted with. a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected solvent such as acetonitrile, THF, 1,4-dioxane, and the like;at a temperature in the range of from about 25° C. to about 100° C.; toyield the corresponding compound of formula (IIIc).

Compounds of formula (III) wherein Z is —NR^(S)—C(NH₂)═N—CN (a guanidinederivative) may be prepared as described in Scheme C-4 below.

Accordingly, a suitably substituted compound of formula (c-7) is reactedwith a suitably selected source of sulfur such as S, P₂S₅, Lawesson'sreagent, and the like; in a suitably selected organic solvent such astoluene, THF, xylene, and the like; at a temperature in the range offrom about 60° C. to about 140° C.; to yield the corresponding compoundof formula (c-13).

The compound of formula (c-13) is reacted with a suitably selectedC₁₋₄alkylating agent such as CH₃I, (CH₃)₂SO₄, CH₃CH₂I, and the like; inthe presence of a suitably selected base such as TEA, DIPEA, K₂CO₃, andthe like; in a suitably selected organic solvent such as DCM, THF, DMF,and the like; at a temperature in the range of from about 25° C. toabout 80° C.; to yield the corresponding compound of formula (c-14),wherein A⁰ is the corresponding C₁₋₄alkyl group.

The compound of formula (c-14) is reacted with cyanoamine, a knowncompound; in the presence of a suitably selected base such as NaH,Cs₂CO₃, t-BuOK, and the like; in a suitably selected organic solventsuch as THF, 1,4-dioxane, DMF, and the like; at a temperature in therange of from about 25° C. to about 80° C.; to yield the correspondingcompound of formula (c-15).

The compound of formula (c-15) is reacted with. a suitably selected acidsuch as pyridine hydrochloride, TMSI, TsOH, and the like; in a suitablyselected solvent such as acetonitrile, THF, 1,4-dioxane, and the like;at a temperature in the range of from about 25° C. to about 100° C.; toyield the corresponding compound of formula (IIId)

Pharmaceutical Compositions

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I), compounds of formula(II) and/or compounds of formula (III) with a pharmaceuticallyacceptable carrier. Pharmaceutical compositions containing one or moreof the compounds of the invention described herein as the activeingredient can be prepared by intimately mixing the compound orcompounds with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending upon the desired route of administration(e.g., oral, parenteral). Thus for liquid oral preparations such assuspensions, elixirs and solutions, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,stabilizers, coloring agents and the like; for solid oral preparations,such as powders, capsules and tablets, suitable carriers and additivesinclude starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like. Solid oral preparations mayalso be coated with substances such as sugars or be enteric-coated so asto modulate major site of absorption. For parenteral administration, thecarrier will usually consist of sterile water and other ingredients maybe added to increase solubility or preservation. Injectable suspensionsor solutions may also be prepared utilizing aqueous carriers along withappropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 0.01 mg to about1000 mg or any amount or range therein, and may be given at a dosage offrom about 0.01 mg/kg/day to about 300 mg/kg/day, or any amount or rangetherein, preferably from about 0.1 mg/kg/day to about 50 mg/kg/day, orany amount or range therein, preferably from about 0.05 mg/kg/day toabout 15 mg/kg/day, or any amount or range therein, preferably fromabout 0.05 mg/kg/day to about 7.5 mg/kg/day, or any amount or rangetherein. The dosages, however, may be varied depending upon therequirement of the patients, the severity of the condition being treatedand the compound being employed. The use of either daily administrationor post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid pre-formulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these pre-formulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid pre-formulation composition is then subdivided into unit dosageforms of the type described above containing from about 0.01 mg to about1,000 mg, or any amount or range therein, of the active ingredient ofthe present invention. The tablets or pills of the novel composition canbe coated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of material can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating disorders described in the present invention mayalso be carried out using a pharmaceutical composition comprising any ofthe compounds as defined herein and a pharmaceutically acceptablecarrier. The pharmaceutical composition may contain between about 0.01mg and about 1000 mg of the compound, or any amount or range therein;preferably from about 1.0 mg to about 500 mg of the compound, or anyamount or range therein, and may be constituted into any form suitablefor the mode of administration selected. Carriers include necessary andinert pharmaceutical excipients, including, but not limited to, binders,suspending agents, lubricants, flavorants, sweeteners, preservatives,dyes, and coatings. Compositions suitable for oral administrationinclude solid forms, such as pills, tablets, caplets, capsules (eachincluding immediate release, timed release and sustained releaseformulations), granules, and powders, and liquid forms, such assolutions, syrups, elixirs, emulsions, and suspensions. Forms useful forparenteral administration include sterile solutions, emulsions andsuspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

To prepare a pharmaceutical composition of the present invention, acompound of formula (I), compound of formula (II) or compound of formula(III), as the active ingredient(s) is intimately admixed with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending of the form of preparation desired for administration (e.g.oral or parenteral). Suitable pharmaceutically acceptable carriers arewell known in the art. Descriptions of some of these pharmaceuticallyacceptable carriers may be found in The Handbook of PharmaceuticalExcipients, published by the American Pharmaceutical Association and thePharmaceutical Society of Great Britain.

Methods of formulating pharmaceutical compositions have been describedin numerous publications such as Pharmaceutical Dosage Forms: Tablets,Second Edition, Revised and Expanded, Volumes 1-3, edited by Liebermanet al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2,edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems,Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

Compounds of the present invention may be administered in any of theforegoing compositions and according to dosage regimens established inthe art whenever treatment of disorders mediated by the EP3 receptor isrequired.

The daily dosage of the products may be varied over a wide range fromabout 0.01 mg to about 1,000 mg per adult human per day, or any amountor range therein. For oral administration, the compositions arepreferably provided in the form of tablets containing, 0.01, 0.05, 0.1,0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. An effective amount of the drugis ordinarily supplied at a dosage level of from about 0.01 mg/kg toabout 500 mg/kg of body weight per day, or any amount or range therein.Preferably, the range is from about 0.05 to about 50.0 mg/kg of bodyweight per day, or any amount or range therein. More preferably, fromabout 0.05 to about 15.0 mg/kg of body weight per day, or any amount orrange therein.

More preferably, from about 0.05 to about 7.5 mg/kg of body weight perday, or any amount or range therein. The compounds may be administeredon a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trialsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

EXAMPLE

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

Example 1 Compound #303 and #304 (Z) and (E)5-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropylidene)oxazolidine-2,4-dione

Step 1: 2-(8-fluoronaphthalen-2-yl)-6-methoxypyridine

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed a solution of1-bromo-3-methoxybenzene (4.5 g, 24.06 mmol, 1.00 equiv) in DME/H₂O(80/20 mL),2-(8-fluoronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.0g, 25.72 mmol, 1.07 equiv), Pd(dppf)Cl₂.CH₂Cl₂ (1 g, 1.23 mmol, 0.05equiv), sodium carbonate (5.1 g, 48.12 mmol, 2.00 equiv). The resultingsolution was stirred for 16 h at 90° C. in an oil bath. The resultingsolution was then extracted with ethyl acetate (3×100 mL) and theorganic layers combined. The resulting mixture was washed with sodiumchloride (aq) (3×100 mL). The resulting mixture was concentrated undervacuum. The reaction target product was detected by LCMS. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(5:95) to yield 2-(8-fluoronaphthalen-2-yl)-6-methoxypyridine as yellowoil.

Mass spectrum (ESI, m/z): Calculated for C₁₆H₁₂FNO, 254.1 [M+H]⁺, found254.0.

Step 2:1-[6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl]-2-methylpropan-1-one

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, were placed a solution of2-(8-fluoronaphthalen-2-yl)-6-methoxypyridine (2.6 g, 10.27 mmol, 1.00equiv) in tetrahydrofuran (80 mL). The resulting solution was stirred at−78° C. in a dry ice bath. n-BuLi (2.5M) (10 mL) was added dropwise. Theresulting solution was stirred for 2 h at −78° C. in a dry ice bath.N-methoxy-N,2-dimethylpropanamide (2.0 g, 15.25 mmol, 1.49 equiv) wasadded dropwise. The resulting solution was stirred for 2 h at −78° C. ina dry ice bath. The reaction was then quenched by the addition of NH₄Cl(aq). The resulting solution was extracted with ethyl acetate (3×100 mL)and the organic layers combined. The resulting mixture was washed withsodium chloride (aq) (3×100 mL). The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:20) to yield1-[6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl]-2-methylpropan-1-oneas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₀H₁₈FNO₂, 324.1 [M+H]⁺, found324.0.

Step 3:5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-1-hydroxy-2-methylpropyl)oxazolidine-2,4-dione

Into a 100 mL three neck round-bottom flask, were placedoxazolidine-2,4-dione (515 mg, 5.096 mmol, 1 equiv.), LiCl (648 mg, 15.3mmol, 3 equiv.) and THF (30 mL). The reaction was purged with an inertatmosphere of nitrogen. The mixture was then added t-BuLi (9.6 mL, 15.3mmol, 1.6M) dropwise with stirring at −78° C. The resulting solution wasstirred for 30 min at −78°.1-(6-(8-Fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-one(500 mg, 1.546 mmol, 0.3 equiv.)/THF (3 mL) was added to above solutionat −78° C. The resulting solution was stirred for 30 min at −78° C. and1 hrs at room temperature. The reaction progress was monitored byTLC/LCMS (DCM/MeOH=20:1). The reaction was then quenched by the additionof 3 mL of NH₄Cl (aqueous). The reaction was extracted with ethylacetate and concentrated under vacuum. The residue was applied onto asilica gel column with DCM/MeOH (5:95) to yield5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-1-hydroxy-2-methylpropyl)oxazolidine-2,4-dioneas a white solid.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₁FN₂O₅, 425.1 (M+H), found425.1.

Step 4: (Z) and(E)-5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropylidene)oxazolidine-2,4-dione

Into a 8-mL vial, were placed5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-1-hydroxy-2-methylpropyl)oxazolidine-2,4-dione(390 mg, 0.919 mmol, 1 equiv.), Py (2.5 mL). SOCl₂ (0.2 mL, 3 equiv) wasadded dropwise at 0° C. The resulting solution was stirred 16 hrs atroom temperature. The reaction progress was monitored by TLC/LCMS. Thesolution was concentrated under vacuum. Sodium carbonate was employed toadjust the pH to 7-8. The resulting solution was extracted with ethylacetate (2×100 ml) and the organic/aqueous layers were combined. Thesolution was concentrated under vacuum. The residue product was purifiedby chromatogram on silica gel with ethyl acetate/petroleum ether (1:3)to yield5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropylidene)oxazolidine-2,4-dioneas a white solid.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₁₉FN₂O₄, 407.1 (M+H), found407.2.

Step 5: (Z) and (E)5-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropylidene)oxazolidine-2,4-dione

Into a 8-mL vial, were placed(Z/E)-5-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methylene)oxazolidine-2,4-dione(50 mg, 0.123 mmol, 1.00 equiv), CH₃CN (3 ml), sodium iodide (92 mg,0.615 mmol, 5 equiv). To the mixture was then addedchlorotrimethylsilane (66 mg, 0.615 mmol, 5.00 equiv) dropwise withstirring at room temperature. The resulting solution was stirred for 2hrs at 25° C. The reaction progress was monitored by LCMS. The reactionwas then quenched by the addition of MeOH (2 mL). The resulting mixturewas concentrated under vacuum. The product was purified by by Prep-HPLCwith the following conditions (1#-Waters 2767-5): Column, SunFire PrepC18, 5 um, 19*100 mm; mobile phase, Water of 0.05% NH₄HCO₃ and CH₃CN(28% CH₃CN up to 38% in 12 min, up to 100% in 2 min, down to 15% in 2min; Detector, 254 nm to yield(E)-5-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropylidene)oxazolidine-2,4-dionea light yellow solid ¹H NMR (300 MHz, CD₃OD) δ: 8.44 (s, 1H), 8.06 (d,J=8.4 Hz, 1H), 7.85-7.89 (m, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.46-7.61 (m,2H), 7.25-7.31 (m, 1H), 6.83 (d, J=10.8 Hz, 1H), 3.15-3.24 (m, 1H), 1.18(brm, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −124.51. Mass spectrum (ESI,m/z): Calculated for C₂₂H₁₇FN₂O₄, 393.1 (M+H), found 393.0

and(Z)-5-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropylidene)oxazolidine-2,4-dioneas a light yellow solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.36 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.78(d, J=8.7 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.41-7.49 (m, 2H), 7.16-7.23(m, 1H), 6.74 (d, J=7.2 Hz, 1H), 4.02-4.11 (m, 1H), 1.04 (d, J=6.9 Hz,6H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −124.40. Mass spectrum (ESI, m/z):Calculated for C₂₂H₁₇FN₂O₄, 393.1 (M+H), found 393.0.

Example 2 Compound #305(E)-5-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropylidene)thiazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 1 step 3, reacting1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-oneand thiazolidine-2,4-dione followed by dehydration and demethylation toyield the product as an off-while solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.35 (s, 1H), 7.96-8.00 (m, 1H), 7.78-7.82(m, 1H), 7.66-7.69 (m, 1H), 7.40-7.49 (m, 1H), 7.17-7.27 (m, 2H), 6.71(d, J=7.2 Hz, 1H), 2.65-2.68 (m, 1H), 0.99-1.02 (m, 6H). ¹⁹F NMR (400MHz, CD₃OD) δ: −123.43. Mass spectrum (ESI, m/z): Calculated forC₂₂H₁₇FN₂O₃S, 409.1 (M+H), found 409.1.

Example 3 Compound #715-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)thiazolidine-2,4-dione

Step 1:5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)thiazolidine-2,4-dione

Into a 50-mL round-bottom flask, were placed(E)-5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropylidene)thiazolidine-2,4-dione(60 mg, 0.142 mmol, 1 equiv), Pd/C (60 mg), AcOH (0.5 mL), 1,4-dioxane(5 mL). To the mixture was then introduced H₂ (g). The resultingsolution was stirred overnight at 25° C. The reaction was monitored byLCMS. A filtration was performed and the filtrate was concentrated undervacuum to yield5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)thiazolidine-2,4-dioneas light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₁FN₂O₃S, 425.1 (M+H),found 425.1.

Step 2:5-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)thiazolidine-2,4-dione

Into a 50-mL round-bottom flask, were placed5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)thiazolidine-2,4-dione(30 mg, 0.071 mmol, 1 equiv.), CH₃CN (5 mL), NaI (21 mg, 0.140 mmol, 2equiv.), TMSCl (15 mg, 0.138 mmol, 2 equiv.). The resulting solution wasstirred 4 h at 25° C. The reaction was monitored by LCMS. The resultingmixture was concentrated under vacuum. The residue was purified byPrep-HPLC with the following conditions (1#-Waters 2767-5): Column,SunFire Prep C18, 5 um, 19*100 mm; mobile phase, Water of 0.05% NH₄HCO₃and CH₃CN (20% CH₃CN up to 50% in 10 min, up to 100% in 2 min, down to20% in 2 min; Detector, 254 nm to yield5-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)thiazolidine-2,4-dioneas off white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.39-8.41 (m, 1H), 8.05-8.08 (m, 1H),7.83-7.88 (m, 1H), 7.75-7.78 (m, 1H), 7.51-7.60 (m, 2H), 7.26-7.32 (m,1H), 6.74-6.79 (m, 1H), 4.95-4.96 (m, 1H), 3.53-3.57 (m, 1H), 2.55-2.58(m, 1H), 1.12-1.15 (m, 3H), 0.85-0.93 (m, 3H). ¹⁹F NMR (300 MHz, CD₃OD)δ: −124.46. Mass spectrum (ESI, m/z): Calculated for C₂₂H₁₉FN₂O₃S, 411.1(M+H), found 411.1.

Example 4 Compound #59 and #60syn-(6-(8-Fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)oxazolidine-2,4-dione andanti-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)oxazolidine

Step 1: ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-oxoacetate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed2-(8-fluoronaphthalen-2-yl)-6-methoxypyridine (3.0 g, 11.845 mmol, 1.00equiv), THF (50 mL). To the mixture was then added t-BuLi (11 mL, 17.6mmol, 1.5 equiv) dropwise with stirring at −78° C. The resultingsolution was stirred 3.0 h at −78° C. ThenN-methoxy-N-methylisobutyramide (2.6 g, 17.791 mmol, 1.5 equiv) wasadded to the mixture and stirred for 3.0 h at −78° C. The reactionprogress was monitored by LCMS. The reaction was then quenched by theaddition of water. The resulting solution was extracted with ethylacetate (3×100 mL) and the organic layers combined. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (5/95) to yieldethyl 2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-oxoacetateas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₀H₁₆FNO₄, 354.1 (M+H), found354.0.

Step 2: Ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)acetate

Into a 50-mL round-bottom flask, were placed ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-oxoacetate (2 g,5.66 mmol, 1 equiv.), TFA (30 mL), Et₃SiH (20 mL) at room temperature.The resulting solution was stirred 6 hrs at 90° C. The reaction progresswas monitored by TLC/LCMS. The solution was concentrated under vacuum.The residue was purified by chromatogram on silica gel with ethylacetate/petroleum ether (20:1) to yield ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)acetate as lightyellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₀H₁₈FNO₃, 340.1 (M+H), found340.1.

Step 3: Ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanoate

Into a 50-mL round-bottom flask, were placed ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)acetate (1.030 g,3.035 mmol, 1 equiv.), DMF (10 mL), potassium 2-methylpropan-2-olate(9.12 mL, 9.12 mmol, 3 equiv.) at room temperature. 2-Iodopropane (1.029g, 6.053 mmol, 2 equiv.) was added at 0° C. The resulting solution wasstirred 3 hrs at room temperature. The reaction progress was monitoredby TLC/LCMS. The resulting solution was extracted with ethyl acetate(2×100 mL) and washed with brine (5×). The organic layers were combined.The solution was concentrated under vacuum. The residue was purified bychromatogram on silica gel with ethyl acetate/petroleum ether (15:1) toyield ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanoateas a yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₄FNO₃, 382.2 (M+H), found382.2.

Step 4:2-(6-(8-Fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-1-ol

Into a 50-mL round-bottom flask, were placed ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanoate(572 mg, 1.500 mmol, 1 equiv), THF (30 mL). LiAlH₄ (3.004 mmol, 2equiv.) was added in portion at 0° C. The resulting solution was stirred1 h at room temperature. The reaction progress was monitored by TLC/LCMS(PE:EA=6:1). The reaction was then quenched by Na₂SO₄.10H₂O. Afiltration was performed and washed with MeOH. The solution wasconcentrated under vacuum. The reaction was extracted with ethyl acetateand dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was purified by chromatogram on silica gel with ethylacetate/petroleum ether (10:1) to yield2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-1-olas a colorless oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₂FNO₂, 340.2 (M+H), found340.1.

Step 5:2-(6-(8-Fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanal

Into a 25-mL round-bottom flask, were placed2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-1-ol(380 mg, 1.120 mmol, 1 equiv.), CH₂Cl₂ (30 mL).(1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.347 g, 3.176mmol, 3 equiv.) was added in portion at room temperature. The resultingsolution was stirred 1 h at room temperature. The reaction progress wasmonitored by TLC/LCMS (PE:EA=6:1). The reaction was then quenched byNa₂S₂O₃/NaHCO₃/H₂O. The reaction was extracted with ethyl acetate anddried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified by chromatogram on silica gel with ethylacetate/petroleum ether (10:1) to yield2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanal asa colorless oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₀FNO₂, 338.1 (M+H), found338.1.

Step 6:3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-hydroxy-4-methylpentanenitrile

Into a 40-mL vial were placed2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanal(300 mg, 0.899 mmol, 1 equiv.), TMSCN (90 mg, 0.899 mmol, 1 equiv.),CH₂Cl₂ (10 mL). The reaction was purged with an inert atmosphere ofnitrogen. To the mixture was then added AlCl₃ (400 mg, 0.89 mmol, 1equiv.), at 0° C. The resulting solution was stirred for 60 min at 0° C.The reaction progress was monitored by TLC (PE:EA=3:1). The reaction wasthen quenched by the addition of water (2 mL). The reaction wasextracted with ethyl acetate and concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(10:90) to yield3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-hydroxy-4-methylpentanenitrile324 mg as a colorless oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₁FN₂O₂, 365.2 (M+H), found365.2.

Step 7:3-(6-(8-fluoronaphthalen-2-yl)-2-hydroxypyridin-3-yl)-2-hydroxy-4-methylpentanoate

Into a 50-mL round-bottom flask were placed3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-hydroxy-4-methylpentanenitrile(200 mg, 0.549 mmol, 1 equiv.), MeOH (10 mL). HCl (4 mL) was addeddropwise. The resulting solution was stirred for 16 hrs min at 80° C.The reaction progress was monitored by TLC/LCMS (PE:EA=1:1). Thesolution was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:1) to yieldmethyl3-(6-(8-fluoronaphthalen-2-yl)-2-hydroxypyridin-3-yl)-2-hydroxy-4-methylpentanoateas a colorless oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂FNO₄, 384.2 (M+H), found384.0.

Step 8:syn-(6-(8-Fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)oxazolidine-2,4-dione andanti-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)oxazolidine

Into a 100-mL round-bottom flask, were placed methyl3-(6-(8-fluoronaphthalen-2-yl)-2-hydroxypyridin-3-yl)-2-hydroxy-4-methylpentanoate(94 mg, 0.245 mmol, 1.00 equiv.), CH₂Cl₂ (4 mL), 2,2,2-trichloroacetylisocyanate (53.7 mg, 0.270 mmol, 1.00 equiv.). The resulting solutionwas stirred for 2 hrs at 25° C. The resulting mixture was concentratedunder vacuum. To the mixture was then added EtOH (4 mL), Et₃N (0.1 mL).The resulting solution was stirred for 4 hrs at 80° C. The reactionprogress was monitored by TLC/LCMS. The resulting mixture wasconcentrated under vacuum. The residue was dissolved in DMF (2 mL). Theresidue was purified by Prep-HPLC with the following conditions(1#-Waters 2767-5): Column, SunFire Prep C18, 5 um, 19*100 mm; mobilephase, Water of 0.05% NH₄HCO₃ acid and CH₃CN (28% CH₃CN up to 32% in 17min, up to 100% in 1 min, down to 28% in 1 min; Detector, 254 nm toyieldsyn-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)oxazolidine-2,4-dioneas a white solid

¹H NMR (400 MHz, CD₃OD) δ: 8.40 (s, 1H), 8.06 (d, J=8.4 Hz, 1H),7.83-7.86 (m, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H),7.52-7.58 (m, 1H), 7.27-7.31 (m, 1H), 6.77 (d, J=7.2 Hz, 1H), 5.23 (d,J=2.8 Hz, 1H), 3.58-3.62 (m, 1H), 2.05-2.25 (m, 1H), 1.26 (d, J=7.2 Hz,3H), 0.92 (d, J=7.2 Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −124.45. Massspectrum (ESI, m/z): Calculated for C₂₂H₁₉FN₂O₄, 395.1 (M+H), found395.1.

andanti-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)oxazolidine-2,4-dioneas a white solid.

1H NMR (400 MHz, CD₃OD) δ: 8.40 (s, 1H), 8.06-8.08 (m, 1H), 7.85-7.88(m, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.63 (d, J=7.2 Hz, 1H), 7.53-7.58 (m,1H), 7.27-7.32 (m, 1H), 6.79 (d, J=7.2 Hz, 1H), 5.28 (d, J=6.0 Hz, 1H),3.56-3.60 (m, 1H), 2.38-2.47 (m, 1H), 1.16 (d, J=6.4 Hz, 3H), 0.92 (d,J=6.8 Hz, 3H). 19F NMR (400 MHz, CD₃OD) δ: −124.40.

Example 5 Compound #62(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Step 1:5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-1-hydroxy-3-methylbutyl)oxazolidine-2,4-dione

To a rapidly stirred solution of lithium chloride (510 mg, 12.030 mmol,3.00 equiv.) and oxazolidine-2,4-dione (380 mg, 3.760 mmol, 1.00 equiv.)in THF (8 mL) under N₂ atmosphere at −78° C. was added t-BuLi (7.5 mL,12.00 mmol, 3.00 equiv) dropwise. The reaction mixture was stirred at−78° C. for 20 minutes then warmed up to 0° C. for 5 minutes. Themixture was recooled to −78° C. and a solution of2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanal(400 mg, 1.186 mmol, 0.30 equiv.) in THF (4 mL) was added. The reactionwas stirred at −78° C. for 30 minutes. The reaction was monitored byTLC. Saturated aq. NH₄Cl was added and the mixture was extracted withEtOAc, and the combined organic layer. The organic layer was dried overNa₂SO₄ and the solvent was evaporated under reduced pressure. Theresidue was purified by column chromatography (DCM/MeOH=20:1) to yield5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-1-hydroxy-3-methylbutyl)oxazolidine-2,4-dioneas a white solid.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₃FN₂O₅, 439.2 (M+H), found439.1.

Step 2:(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Into a 25-mL round-bottom flask, were placed5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-1-hydroxy-3-methylbutyl)oxazolidine-2,4-dione(30 mg, 0.068 mmol, 1.00 equiv.) in pyridine, then sulfurous dichloride(24 mg, 0.202 mmol, 3.00 equiv) was added to the former solution at 0°C. The resulting solution was stirred for 4.5 h at room temperature. Thereaction was monitored by TLC. The solvent was evaporated under reducedpressure. The residue was purified by column chromatography(DCM/MeOH=20:1) to yield(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dioneas a dark brown solid.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₁FN₂O₄, 421.1 (M+H), found421.0.

Step 3:(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Into a 25-mL round-bottom flask, were placed a solution of(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione(60 mg, 0.143 mmol, 1.00 equiv.), NaI (44 mg, 0.294 mmol, 2.00 equiv.)in CH₃CN (8 mL), then TMSCl (32 mg, 0.295 mmol, 2.00 equiv.) was added.The resulting solution was stirred for 3.5 h at 30° C., and the reactionwas monitored by LCMS. MeOH (0.5 mL) was added to the mixture and themixture was stirred for 10 minutes at room temperature. The resultingmixture was evaporated under reduced pressure. The residual was purifiedby Prep-HPLC with the following conditions: (1#waters2767-5): Column,SunFire Prep C18, 19*150 mm 5 umH PrepC-001(T)18600256819513816414 04;mobile phase, Phase A: water with 0.05% NH₄HCO₃; Phase B: CH₃CN (27%CH₃CN up to 33% in 10 min, up to 95% CH₃CN in 0.1 min, hold 95% in 1.9min, down to 27% CH₃CN in 0.1 min, hold 27% in 1.9 min); Detector, UV220& 254 nm to yield(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dioneobtained as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.35 (s, 1H), 8.01-8.04 (m, 1H), 7.79-7.83(m, 1H), 7.71-7.74 (m, 1H), 7.47-7.59 (m, 2H), 7.22-7.28 (m, 1H), 6.74(d, J=7.2 Hz, 1H), 6.35 (d, J=10.8 Hz, 1H), 3.50-3.72 (m, 1H), 2.31-2.42(m, 1H), 0.98 (d, J=6.6 Hz, 3H), 0.88 (d, J=7.5 Hz, 3H). ¹⁹F NMR (300MHz, CD₃OD) δ: −77.17,−124.47. Mass spectrum (ESI, m/z): Calculated forC₂₃H₁₉FN₂O₄, 407.1 [M−2.14CF₃COOH+H], found 407.1.

Example 6 Compound #78 and #79(R*,Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione and(S*,Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione as a racemate (200 mg) was purified by chiral SFC(CHIRALPAK AD-H 5 μM 250×20 mm) using mobile phase of Hex (0.1% TFA) andIPA (hold 5.0% IPA in 14 min) method and detector at UV 254/220 nm toyield the corresponding R* enantiomer and S* enantiomer as white solids.Absolute stereochemistry was arbitually assigned. The solids were thenindividually dissolved in water (10 mL) and ACN (2 mL) and dried bylypholizer to yield (R*,Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione as a light yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 12.43 (s, 1H), 8.62 (s, 1H), 8.25 (d, J=8.6Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.66-7.79 (m,2H), 7.50-7.60 (m, 1H), 6.88-7.03 (m, 1H), 6.48 (d, J=10.9 Hz, 1H),3.70-3.84 (m, 1H), 2.32-2.47 (m, 1H), 1.07 (d, J=6.6 Hz, 3H), 0.98 (d,J=6.6 Hz, 3H). ¹⁹F NMR (300 MHz, DMSO) δ: −122.23. Mass spectrum (ESI,m/z): Calculated for C₂₃H₂₀ClFN₂O₄, 407.1 (M+H), found 407.1.

and (S*,Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dioneas light yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 12.33 (s, 1H), 8.51 (s, 1H), 8.14 (d, J=8.8Hz, 1H), 8.06-7.97 (m, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.43-7.59 (m, 2H),7.31-7.40 (m, 1H), 6.81-6.85 (m, 1H), 6.37 (d, J=11.0 Hz, 1H), 3.67 (t,J=8.9 Hz, 1H), 2.23-2.29 (m, 1H), 0.92 (d, J=6.6 Hz, 3H), 0.83 (d, J=6.6Hz, 3H). ¹⁹F NMR (300 MHz, DMSO) δ: −122.23. Mass spectrum (ESI, m/z):Calculated for C₂₃H₂₀ClFN₂O₄, 407.1 (M+H), found 407.1.

Example 7 Compound #63(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)thiazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 step 1, reacting2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanaland thiazolidine-2,4-dione followed by dehydration and demethylation toyield the product as an off-yellow solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.43 (s, 1H), 8.07 (d, J=8.8 Hz,1H), 7.87 (d,J=8.8 Hz,1H), 7.77 (d, J=8.4 Hz,1H), 7.53-7.60 (m, 2H), 7.21-7.32 (m,2H), 6.79 (d, J=7.2 Hz,1H), 3.32-3.38 (m, 1H), 2.35-2.45 (m, 1H), 1.04(d, J=6.4 Hz,3H), 0.95 (d, J=6.8 Hz,3H). ¹⁹F NMR (400 MHz, CD₃OD) δ:−124.42.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₁₉FN₂O₃S, 423.1 (M+H),found 423.0.

Example 8 Compound #81 and #74Syn-3-(1-(1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-oneandanti-3-(1-(1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

Step 1: Syn-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl) oxazolidine-2,4-dione andanti-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dione

Into a 50-mL round-bottom flask, were placed a solution of(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione(20 mg, 0.048 mmol, 1.00 equiv.) in ethyl acetate (10 mL), Palladiumcarbon (20 mg). To the mixture was then introduced hydrogen gas. Theresulting solution was stirred for 16 h at 25° C. The solids werefiltered out. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with DCM/MeOH (20/1) toyield5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dioneas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₃FN₂O₄, 423.2 (M+H), found423.2.

Step 2:Syn-3-(1-(1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-oneandanti-3-(1-(1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

The title compounds were prepared according to the procedure asdescribed in Example 1 step 5 by demethylation of5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dione with TMSCl/NaI in CH₃CN to yield the compounds asoff-yellow solids.

Syn-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dione:¹H NMR (400 MHz,CD₃OD) δ: 8.43 (s, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.86 (d,J=7.2 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.53-7.58 (m, 2H), 7.28-7.35 (m,1H), 6.80 (d, J=7.2 Hz, 1H), 4.70-4.73 (m, 1H), 2.90-2.92 (m, 1H),2.52-2.59 (m, 1H), 2.09-2.14 (m, 2H), 1.02 (d, J=6.6 Hz, 3H), 0.91 (d,J=6.6 Hz, 3H). ¹⁹F NMR (400 MHz,CD₃OD) δ: −124.52. Mass spectrum (ESI,m/z): Calculated for C₂₃H₂₁FN₂O₄, 409.1 (M+H), found 409.1.

Anti-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dione:¹H NMR (400 MHz,CD₃OD) δ: 8.43 (s, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.87 (d,J=7.2 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.52-7.69 (m, 2H), 7.28-7.32 (m,1H), 6.77 (d, J=6.8 Hz, 1H), 4.77-4.80 (m, 1H), 2.98-3.00 (m, 1H),2.38-2.41 (m, 2H), 2.08-2.18 (m, 1H), 1.04 (d, J=6.4 Hz, 3H), 0.89 (d,J=6.4 Hz, 3H). ¹⁹F NMR (400 MHz,CD₃OD) δ: −124.52. Mass spectrum (ESI,m/z): Calculated for C₂₃H₂₁FN₂O₄, 409.1 (M+H), found 409.1.

Example 9 Compound #102 and #83(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dioneand(Z)-5-(2-(5-bromo-6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Step 1:(E)-5-(2-(5-bromo-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Into a 40-mL vial maintained with an inert atmosphere of nitrogen, wereplaced(E)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione(200 mg, 0.47 mmol, 1 equiv.), NBS (100 mg, 0.57 mmol, 1.2 equiv.), MeOH(5 mL), CH₃CN (5 mL), TFA (1 mL). The resulting solution was stirred for16 h at 60° C. The mixture was concentrated under vacuum. The residuewas purified purified by TLC with ethyl acetate/petroleum ether (1:6) toyield(E)-5-(2-(5-bromo-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dioneas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₀BrFN₂O₄, 499.1(M+H),499.1.

Step 2:(E)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxy-5-methylpyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Into a 40-mL vial purged and maintained with an inert atmosphere ofnitrogen, were placed(E)-5-(2-(5-bromo-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione(120 mg, 0.24 mmol, 1 equiv), DMF (5 mL), Pd(OAc)₂(3 mg, 0.013 mmol,0.05 equiv), (o-tol)₃P (7 mg, 0.023 mmol, 0.1 equiv), Sn(CH₃)₄(86 mg,0.48 mmol, 2 equiv). The resulting solution was stirred with 16 h at100° C. The mixture was quenched by the addition of H₂O, extracted withEA. The organic layer was concentrated under vacuum. The residue waspurified by TLC with ethyl acetate/petroleum ether (1:6) to yield(E)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxy-5-methylpyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dioneas yellow oil. Mass spectrum (ESI, m/z): Calculated for C₂₅H₂₃FN₂O₄,435.5(M+H), 435.1.

Step 3:(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dioneand(Z)-5-(2-(5-bromo-6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compounds were prepared according to the procedure asdescribed in Example 1 step 5 by demethylation of(E)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxy-5-methylpyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dioneand(E)-5-(2-(5-bromo-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dionewith TMSCl/NaI in CH₃CN to yield the(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dioneas a light yellow solid oil.

¹H NMR (300 MHz,CD₃OD) δ: 8.12 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.74 (d,J=8.4 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.48-7.50 (m, 1H), 7.44 (s, 1H),7.22-7.23 (m, 1H), 6.02 (d, J=10.5 Hz, 1H), 3.69-3.75 (m, 1H), 2.25-2.29(m, 1H), 2.11 (s, 3H), 0.82-0.97 (m, 6H). ¹⁹F NMR (300 MHz,CD₃OD) δ:−124.93. Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₁FN₂O₄,421.1(M+H), 421.0.

and(Z)-5-(2-(5-bromo-6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dioneas a light yellow oil.

¹H NMR (300 MHz,CD₃OD) δ: 8.20 (s, 1H), 8.01 (d, J=9.0 Hz, 1H), 7.74 (d,J=8.1 Hz, 1H), 7.51-7.63 (m, 2H), 7.41-7.49 (m, 1H), 7.22-7.28 (m, 1H),5.88 (d, J=9.6 Hz, 1H), 3.67-3.73 (m, 1H), 2.23-2.32 (m, 1H), 0.84-0.97(m, 6H). ¹⁹F NMR (300 MHz,CD₃OD) δ: −76.95, −124.93. Mass spectrum (ESI,m/z): Calculated for C₂₃H₁₈BrFN₂O₄, 486.9 (M−0.08CF₃COOH+H), 486.9.

Example 10 Compound #112(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation of5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxy-5-methylpyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dionefollowed by demethylation of5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxy-5-methylpyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dionewith TMSCl/NaI in CH₃CN to yield an off-yellow solid.

¹H NMR (300 MHz, CD₃OD) δ 8.13-8.14 (m, 1H), 8.02-8.05 (m, 1H),7.74-7.76 (m, 1H), 7.58-7.61 (m, 1H), 7.48-7.51 (m, 1H), 7.36-7.38 (m,1H), 7.22-7.28 (m, 1H), 4.70-4.87 (m, 1H), 2.75-2.92 (m, 1H), 2.33-2.49(m, 2H), 2.12-2.17 (m, 1H), 2.07-2.08 (m, 3H), 0.97-1.01 (m, 3H),0.84-0.87 (m, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −124.98. Mass spectrum(ESI, m/z): Calculated for C₂₄H₂₃FN₂O₄, 423.2(M+H), 423.2.

Example 11 Compound #64 and #65Syn-6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)thiazolidine-2,4-dioneandAnti-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)thiazolidine-2,4-dione

The title compounds were prepared according to the procedure asdescribed in Example 8 step 1 by hydrogenation of(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)thiazolidine-2,4-dionefollowed by demethylation of5-(2-(6-(8-fluoro-naphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)thiazolidine-2,4-dionewith TMSCl/NaI in CH₃CN to yieldSyn-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)thiazolidine-2,4-dioneas a light pink solid

¹H NMR (300 Hz, CD₃OD) δ: 8.39 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.83 (d,J=6.9 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.48-7.52 (m, 2H), 7.20-7.35 (m,1H), 6.73 (d, J=7.2 Hz, 1H), 4.25-4.37 (m, 1H), 2.80-2.92 (m, 1H),2.59-2.72 (m, 1H), 2.30-2.42 (m, 1H), 2.01-2.18 (m, 1H), 1.01 (d, J=6.6Hz, 3H), 0.82 (d, J=6.6 Hz, 3H). ¹⁹F NMR (300 Hz, CD₃OD) δ: −76.90,−124.42. Mass spectrum (ESI, m/z): Calculated forC_(25.16)H_(22.08)F_(4.24)N₂O_(5.16)S, 425.1 (M−1.08CF₃COOH+H), found425.1.

andAnti-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)thiazo-lidine-2,4-dionetrifluoroacetic acid as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.39 (s, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.83(d, J=8.7 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.50-7.54 (m, 2H), 7.24-7.28m, 1H), 6.78 (d, J=7.2 Hz, 1H), 4.02-4.07 (m, 1H), 2.60-2.85 (m, 2H),1.95-2.21 (m, 2H), 0.99 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.6 Hz, 3H). ¹⁹FNMR (300 MHz, CD₃OD) δ: −76.90, −124.46. Mass spectrum (ESI, m/z):Calculated for C_(24.48)H_(21.74)F_(3.22)N₂O_(4.48)S, 425.1(M−0.74CF₃COOH+H), found 425.0.

Example 12 Compound #2625-((6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-isopropyloxazolidine-2,4-dione

Step 1: 6-(8-fluoronaphthalen-2-yl)-2-methoxynicotinaldehyde as a yellowsolid

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed a solution of2-(8-fluoronaphthalen-2-yl)-6-methoxypyridine (2 g, 7.897 mmol, 1.00equiv) in tetrahydrofuran (20 mL) and stirred at −78° C. in a dryice/EtOH bath. n-BuLi (4.7 mL, 11.75 mmol, 1.50 equiv) was addeddropwise at −78° C. The resulting solution was stirred for 3 h at −78°C. in a dry ice/EtOH bath. N,N-dimethylformamide (1.23 mL, 15.902 mmol,2.00 equiv) was added dropwise. The resulting solution was stirred for 3h. The reaction was monitored by LCMS. Saturated aq NH₄Cl was added andthe mixture was extracted with EtOAc, and the combined organic layer.The organic layer was dried over Na₂SO₄ and the solvent was evaporatedunder reduced pressure. The residue was purified by columnchromatography (ethyl acetate/petroleum ether=5:95) to yield6-(8-fluoronaphthalen-2-yl)-2-methoxynicotinaldehyde as a yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₁₇H₁₂FNO₂, 282.1 (M+H), found282.1.

Step 2: (E)-ethyl3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)acrylate

To a solution of ethyl 2-(trimethylsilyl)acetate (910 mg, 5.677 mmol,2.00 equiv.) in dry THF (8 mL) was added Lithiumbis(trimethylsilyl)amide (5.70 mL, 2.00 equiv) at −78° C., under anargon atmosphere, into a 25-mL round-bottom flask (the flask wasevacuated and flushed three times with nitrogen), and the reactionmixture was stirred at this temperature for 30 min.6-(8-Fluoronaphthalen-2-yl)-2-methoxynicotinaldehyde (800 mg, 2.844mmol, 1.00 equiv.) in dry THF (8 mL) was added and the reaction wasstirred for another 30 min. The reaction progress was monitored by LCMS.A saturated solution of NH₄Cl was added to the reaction mixture. Theresulting solution was extracted with ethyl acetate. The organic layerswere combined, washed with Na₂SO₄ (aq.) and brine, dried andconcentrated under vacuum. The residue was applied on a silica gelcolumn and eluted with EA/PE(5:95) to yield (E)-ethyl3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)acrylate as ayellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₁₆FNO₃, 352.1 (M+H), found352.0.

Step 3: ethyl3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)propanoate

Into a 50-mL round-bottom flask, were placed (E)-ethyl3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)acrylate (480 mg,1.366 mmol, 1.00 equiv.), Pd—C and ethyl acetate. To the mixture wasthen added H₂. The resulting solution was stirred for 4 h at roomtemperature. The reaction was monitored by LCMS. The solids werefiltered out. The resulting solution was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (5:95) to yield ethyl3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)propanoate asyellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₀FNO₃, 354.1 (M+H), found354.0.

Step 4: 2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)ethanol

Into a 100-ml round bottom flask, were placed a solution of ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)acetate (1.5 g,4.42 mmol, 1.00 equiv.) in THF. LAH (340 mg, 8.598 mmol, 2.00 equiv.) inTHF was added at 0° C. The resulting solution was stirred for 1.5 h atroom temperature. The reaction was monitored by LCMS. The reaction wasquenched by the addition of Na₂SO₄.10H₂O, and the mixture was filteredand dried by Na₂SO₄. The filtrate was combined and concentrated undervacuum to yield2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)ethanol as a yellowoil.

Mass spectrum (EI, m/z): Calculated for C₁₈H₁₆FNO₂, 298.1 (M+H), found297.9.

Step 5:2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)acetaldehyde

Into a 100-ml round bottom flask, were placed a solution of2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)ethanol (1.1 g,3.70 mmol, 1.00 equiv.) and Dess-Martin periodinane (4.7 mg, 11.08 mmol,3.00 equiv.) in dichloromethane (60 ml). The resulting solution wasstirred for 1.5 h at 25° C. The reaction was monitored by LCMS. Themixture was quenched by the addition of saturated Na₂S₂O₃.5H₂O—NaHCO₃solution, stirred for 15 minutes at room temperature until the mixturechanged clear. The resulting solution was extracted with DCM. Theorganic layers were combined, and concentrated under vacuum to yield2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)acetaldehyde as ayellow oil which was used in the next step without further purification.

Mass spectrum (EI, m/z): Calculated for C₁₈H₁₄FNO₂, 296.1 (M+H), found296.0.

Step 6:1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-2-ol

To a rapidly stirred solution of2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)acetaldehyde (1.02g, 3.454 mmol, 1.00 equiv.) in THF (25 mL) under N₂ atmosphere at 0° C.was added isopropylmagnesium chloride (5.1 mL, 10.2 mmol, 3.00 equiv.).The reaction mixture was stirred overnight at 25° C. The reaction wasmonitored by LCMS. Saturated aq. NH₄Cl was added and the mixture wasextracted with EtOAc, and the organic layers combined. The organic layerwas dried over Na₂SO₄ and the solvent was evaporated under reducedpressure. The residue was purified by column chromatography ethylacetate/petroleum ether (1:6) to yield1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-2-olas a yellow solid.

Mass spectrum (EI, m/z): Calculated for C₂₁H₂₂FNO₂, 340.2 (M+H), found340.1.

Step 7: 1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-2-one

Into a 50-ml round bottom flask, were placed a solution of1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-2-ol(320 mg, 0.943 mmol, 1.00 equiv.) and Dess-Martin periodinane (1.2 g,2.829 mmol, 3.00 equiv.) in dichloromethane (10 mL). The resultingsolution was stirred for 2 h at room temperature. The reaction wasmonitored by LCMS. The mixture was quenched by the addition of saturatedNa₂S₂O₃.5H₂O—NaHCO₃ solution, stirred for 20 minutes at room temperatureuntil the mixture changed clear. The resulting solution was extractedwith DCM. The organic layers were combined, and concentrated undervacuum. The residue was applied on a silica gel column (EA: PE=1:3) toyield1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-2-oneas a yellow solid.

Mass spectrum (EI, m/z): Calculated for C₂₁H₂₀FNO₂, 338.1 (M+H), found338.4.

Step 8:2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-2-hydroxy-3-methylbutanenitrile

To a rapidly stirred solution of aluminiumtrichloride (43.474 mg, 0.326mmol, 1.00 equiv.) in DCM (4 ml) under N₂ atmosphere at 0° C. was added1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-2-one(110 mg, 0.326 mmol, 1.00 equiv.) in DCM (2 mL) dropwise.Trimethylsilanecarbonitrile (97.034 mg, 0.978 mmol, 3.00 equiv.) wasthen added to the solution. The reaction mixture was stirred at 0° C.for 1.5 h. The reaction was monitored by LCMS. The resulting solutionwas extracted with DCM. The organic layers were combined, andconcentrated under vacuum. The residue was applied on a silica gelcolumn (EA: PE=1:6) to yield2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-2-hydroxy-3-methylbutanenitrileas a yellow solid.

Mass spectrum (EI, m/z): Calculated for C₂₂H₂₁FN₂O₂, 365.2 (M+H), found365.1.

Step 9: Methyl2-((6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-hydroxy-3-methylbutanoate

Into a 25-mL round-bottom flask, were placed a solution of2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-2-hydroxy-3-methylbutanenitrile(45 mg, 0.123 mmol, 1.00 equiv.) in methanol (4 mL) and hydrogenchloride (0.75 mL). The resulting solution was stirred overnight at 80°C. The reaction was monitored by TLC. The resulting solution wasconcentrated and then extracted with EA. The organic layers werecombined, and concentrated under vacuum. The residue was applied on asilica gel column (DCM:MeOH=20:1) to yield methyl2-((6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-hydroxy-3-methylbutanoateas a colorless oil.

Mass spectrum (EI, m/z): Calculated for C₂₂H₂₂FNO₄, 384.2 (M+H), found384.0.

Step 10:5-((6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-isopropyloxazolidine-2,4-dione

Into a 25-mL round-bottom flask, were placed a solution of methyl2-((6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-hydroxy-3-methylbutanoate(31 mg, 0.081 mmol, 1.00 equiv.) in dichloromethane (5 mL). The reactionwas cooled to 0° C. and 2,2,2-trichloroacetyl isocyanate (30 mg, 0.159mmol, 2.00 equiv.) was added to the solution at this temperature. Afterwarmed to room temperature, the reaction mixture was stirred overnight.The reaction was quenched with methanol (1 mL). The solvents wereremoved under vacuum and the residue was dissolved in ethanol (5 mL).Triethylamine (16 mg, 0.158 mmol, 2.00 equiv.) was added to the mixture.The resulting mixture was stirred for 3 h at 90° C. The resultingsolution was concentrated under vacuum and the residue was purified byPrep-HPLC with the following conditions: (1#waters2767-5): Column,SunFire Prep C18, 19*150 mm 5 umH PrepC-001(T)18600256819513816414 04;mobile phase, Phase A: water with 0.05% NH₄HCO₃; Phase B: CH₃CN (17%CH₃CN up to 40% in 10 min, up to 95% CH₃CN in 0.1 min, hold 95% in 1.9min, down to 17% CH₃CN in 0.1 min, hold 17% in 1.9 min); Detector, UV220& 254 nm to yield5-((6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-isopropyloxazolidine-2,4-dioneas a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.41 (s, 1 H), 8.07 (d, J=7.6 Hz, 1 H), 7.88(d, J=8.0 Hz, 1 H), 7.77 (d, J=8.4 Hz, 1 H), 7.53-7.62 (m, 2 H),7.30-7.32 (m, 1 H), 6.74 (d, J=6.8 Hz, 1 H), 3.35 (d, J=7.2 Hz, 1 H),3.17 (d, J=7.2 Hz, 1 H), 2.24-2.33 (m, 1 H), 1.23 (d, J=7.2 Hz, 3 H),1.17 (d, J=6.4 Hz, 3 H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −124.46. Massspectrum (EI, m/z): Calculated for C₂₂H₁₉FN₂O₄, 395.1 (M+H), found395.0.

Example 13 Compound #306(E)-5-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutan-2-ylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 1 reacting1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-2-oneand oxazolidine-2,4-dione followed by dehydration and demethylation toyield the product as a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.40 (s, 1 H), 8.05 (d, J=8.8 Hz, 1 H),7.83-7.85 (m, 1 H), 7.75 (d, J=8.4 Hz, 1 H), 7.47-7.56 (m, 2 H),7.25-7.30 (m, 1 H), 6.76 (d, J=7.2 Hz, 1 H), 4.05-4.12 (m, 1 H), 3.57(s, 2 H), 1.17 (d, J=6.8 Hz, 6 H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −76.96,−124.50. Mass spectrum (EI, m/z): Calculated forC_(23.86)H_(19.43)F_(2.29)N₂O_(4.86), 407.1 (M−0.43CF₃COOH+H), found407.0.

Example 14 Compound #3085-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutan-2-yl)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation of(E)-5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-2-ylidene)oxazolidine-2,4-dione followed by demethylation of5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-2-yl)oxazolidine-2,4-dionewith TMSCl/NaI in CH₃CN to yield the product as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.36 (s, 1 H), 8.01 (d, J=9.0 Hz, 1 H), 7.81(d, J=7.8 Hz, 1 H), 7.73 (d, J=8.1 Hz, 1 H), 7.44-7.56 (m, 2 H),7.21-7.28 (m, 1 H), 6.63-6.72 (m, 1 H), 4.90-5.00 (m, 1H), 2.46-2.94 (m,4 H), 1.87-1.90 (m, 1 H), 1.01-1.08 (m, 6 H). ¹⁹F NMR (300 MHz, CD₃OD)δ: −76.91, −124.54. Mass spectrum (ESI, m/z): Calculated forC_(24.42)H_(21.71)F_(3.13)N₂O_(5.42), 409.1 (M−0.71CF₃COOH+H), found408.9.

Example 15 Compound #805-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)-1-methylimidazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 1 reacting2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanaland 1-methylimidazolidine-2,4-dione followed by dehydration anddemethylation to yield the product as a white solid.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₄FN₃O₃, 420.2 (M+H), found420.1. ¹H NMR (400 MHz, CD₃OD) δ: 8.38 (s, 1H), 8.04-8.06 (m, 1H),7.82-7.86 (m, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.61-7.64 (m, 1H), 7.52-7.56(m, 1H), 7.25-7.30 (m, 1H), 6.81 (d, J=7.2 Hz, 1H), 6.06 (d, J=10.8 Hz,1H), 4.45-4.51 (m, 1H), 3.42 (s, 3H), 2.43-2.53 (m, 1H), 1.00 (d, J=6.8Hz, 3H), 0.89 (d, J=4 Hz, 3H). The isomer: ¹H NMR (400 MHz, CD₃OD) δ:8.38 (s, 1H), 8.04-8.06 (m, 1H), 7.82-7.86 (m, 1H), 7.75 (d, J=8.4 Hz,1H), 7.61-7.64 (m, 1H), 7.52-7.56 (m, 1H), 7.25-7.30 (m, 1H), 6.72 (d,J=7.2 Hz, 1H), 5.97 (d, J=11.6 Hz, 1H), 4.15-4.21 (m, 1H), 3.06 (s, 3H),2.13-2.20 (m, 1H), 1.05 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.4 Hz, 3H). ¹⁹FNMR (400 MHz, CD₃OD) δ: −124.47.

Example 16 Compound #735-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)-1-methylimidazo-lidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation of5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)-1-methylimidazolidine-2,4-dioneto yield the product as a white solid.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₄FN₃O₃, 422.2 (M+H), found422.2. ¹H NMR (400 MHz, CD₃OD) δ: 8.42 (s, 1H), 8.06 (d, J=8.8 Hz,1H),7.85-7.88 (m, 1H), 7.77 (d, J=8 Hz, 1H), 7.47-7.88 (m, 2H), 7.27-7.32(m, 1H), 6.75 (d, J=7.2 Hz, 1H), 4.01-4.02 (m, 1H), 2.92 (s, 3H),2.73-2.89 (m, 1H), 2.40-2.55 (m, 1H), 2.18-2.30 (m, 2H), 1.03-1.06 (m,3H), 0.84-0.88 (m, 3H). The isomer: ¹H NMR (400 MHz, CD₃OD) δ: 8.42 (s,1H), 8.06 (d, J=8.8 Hz,1H), 7.85-7.88 (m, 1H), 7.77 (d, J=8 Hz, 1H),7.47-7.88 (m, 2H), 7.27-7.32 (m, 1H), 6.71 (d, J=7.2 Hz, 1H), 3.90-3.92(m, 1H), 2.73-2.89 (m, 1H), 2.68 (s, 3H), 2.40-2.55 (m, 1H), 1.98-2.15(m, 2H), 1.03-1.06 (m, 3H), 0.84-0.88 (m, 3H). ¹⁹F NMR (400 MHz, CD₃OD)δ: −126.051.

Example 17 Compound #895-(2-(6-(8-Fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)imidazolidine-2,4-dione

Step 1:5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)imidazolidine-2,4-dione

Into a seal tube were placed3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentanal(68 mg, 0.194 mmol, 1 equiv.), ammoniumcarbonate (122 mg, 1.325 mmol, 4equiv.), ammoniumhydroxide (1 mL), Trimethylsilylcyanide (0.5 mL) inEtOH (2 mL). The reaction mixture was stirred overnight at 100° C. Thereaction was monitored by LCMS. The reaction mixture was concentratedunder vacuum. The residue was purified by thin layer chromatographydeveloped with DCM/MeOH (20/1) to yield5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)imidazolidine-2,4-dioneas yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₄FN₃O₃, 422.2 (M+H), found422.1.

Step 2:5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)imidazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation of5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)imidazolidine-2,4-dione with TMSCl/NaI to yield the product as a whitesolid.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₂FN₃O₃, 408.2 (M+H), found408.2. ¹H NMR (400 MHz, CD₃OD) δ: 8.45 (s, 1H), 8.08 (d, J=8 Hz, 1H),7.87-7.89 (m, 1H), 7.78 (d, J=8 Hz, 1H), 7.53-7.63 (m, 2H), 7.28-7.33(m, 1H), 6.86 (d, J=7.2 Hz, 1H), 3.79-3.83 (m, 1H), 2.88-2.93 (m, 1H),2.24-2.31 (m, 1H), 1.95-2.09 (m, 2H), 1.04 (d, J=6.4 Hz, 3H), 0.91 (d,J=6.8 Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −124.49.

Example 18 Compound #1325-(1-(6-(8-Fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)imidazolidine-2,4-dione

Step 1:(Z)-6-(8-fluoronaphthalen-2-yl)-2-methoxy-3-(1-methoxy-3-methylbut-1-en-2-yl)pyridine

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was added (methoxymethyl)triphenylphosphoniumchloride (63 mg, 0.184 mmol, 2 equiv.), THF (5 mL). This was followed bythe addition LiHMDS (0.02 mL, 0.02 mmol, 2.5 equiv.) dropwise withstirring at 0° C. The reaction was stirred 1 h at 0° C.1-(6-(8-Fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-one(30 mg, 0.093 mmol, 1 equiv.) in THF was added to above mixturesolution. The reaction was stirred overnight at 0° C. The reactionprogress was monitored by TLC (PE:EA=10:1). The reaction was thenquenched by the addition of H₂O (5 mL), extracted with ethyl acetate andthe organic layers combined. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withPE:EA=10:1 to yield(Z)-6-(8-fluoronaphthalen-2-yl)-2-methoxy-3-(1-methoxy-3-methylbut-1-en-2-yl)pyridineas a light yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂FNO₂, 352.2 (M+H), found352.2.

Step 2:2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanal

Into a 50-mL round-bottom flask, were placed(Z)-6-(8-fluoronaphthalen-2-yl)-2-methoxy-3-(1-methoxy-3-methylbut-1-en-2-yl)pyridine(30 mg, 0.085 mmol, 1 equiv), HCl (1 mL), THF (4 mL). The resultingsolution was stirred 2 h at 25° C. The reaction was monitored by LCMS.The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column with PE:EA=10:1 to yield2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanal asa light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₀FNO₂, 338.1 (M+H), found338.1.

Step 3:5-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)imidazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 17 step 1 by cyclization of2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanaland TMSCN/(NH₄)₂CO₃ followed by demethylation of1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)imidazolidine-2,4-dionewith TMSCl/NaI to yield the product as a white solid.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₀FN₃O₃, 394.1 (M+H), found394.1.

Example 19 Compound #695-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)-1-methylimidazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 step 1 by reacting methylimidazolidine-2,4-dione with(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-onewith LDA, dehydrating5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-1-hydroxy-2-methylpropyl)-1-methylimidazolidine-2,4-dione and hydrogenating(E)-5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropylidene)-1-methylimidazolidine-2,4-dione,followed by demethylation of5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-1-methylimidazolidine-2,4-dionewith TMSCl/NaI to yield the product as light yellow solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.40 (s, 1H), 8.06 (d, J=8.4 Hz, 1H),7.82-7.86 (m, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.53-7.58 (m, 2H), 7.26-7.32(m, 1H), 6.74 (d, J=7.2 Hz, 1H), 4.42-4.45 (m, 1H), 3.50-3.60 (m, 1H),2.99 (s, 3H), 2.55-2.60 (m, 1H), 1.29 (d, J=6.6 Hz, 3H), 0.87 (d, J=6.6Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₂FN₃O₃, 408.1(M+H), found 408.1.

Example 20 Compound #2(Z)-5-(2-(6-(8-fluoronaphthalen-2-v)-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropylidene) oxazolidine-2,4-dione

Step 1:2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropanoate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)acetate (200 mg,0.589 mmol, 1 equiv.), THF (10 ml). This was followed by the additiont-BuOK (1.76 ml, 1.76 mmol, 3 equiv.), dropwise with stirring at 0° C.Then, CH₃I (420 mg, 2.959 mmol, 5 equiv.) was added to above solution.The resulting solution was stirred overnight at 25° C. The reactionprogress was monitored by LCMS. The reaction was then quenched by theaddition of H₂O (10 mL), extracted with ethyl acetate and the organiclayers combined. The resulting mixture was concentrated under vacuum.The residue was applied onto a silica gel column with PE:EA=6:1 to yieldethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropanoateas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂FNO₃, 368.2 (M+H), found368.1.

Step 2:2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-ol

Into a 100-mL round-bottom flask purged was ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropanoate(200 mg, 0.544 mmol, 1 equiv.), THF (8 ml), LAH (41 mg, 1.080 mmol, 2equiv.). The resulting solution was stirred 1 h at 25° C. The reactionwas monitored by TLC (PE:EA=4:1). The reaction was then quenched by theaddition of Na₂SO₄/10H₂O (30 mg). The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withPE:EA=6:1 to yield2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-olas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₀H₂₀FNO₂, 326.1 (M+H), found326.1.

Step 3:2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropanal

Into a 100-mL round-bottom flask purged was2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-ol(170 mg, 0.522 mmol, 1 equiv.), DCM (10 mL), DMP (444 mg, 1.047 mmol, 2equiv.). The resulting solution was stirred overnight at 25° C. Thereaction was monitored by TLC (PE:EA=4:1). The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with PE:EA=6:1 to yield2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropanalas light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₀H₁₈FNO₂, 324.1 (M+H), found324.1.

Step 4:(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropylidene) oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 step 1 by reacting oxazolidine-2,4-dione with2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropanalby t-BuLi, dehydrating5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-1-hydroxy-2-methylpropyl)oxazolidine-2,4-dione,followed by demethylation of(E)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropylidene)oxazolidine-2,4-dione with TMSCl/NaI to yield the product asa white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.42 (s, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.87(d, J=8.8 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H),7.52-7.58 (m, 1H), 7.27-7.31 (m, 1H), 6.77 (d, J=7.6 Hz, 1H), 5.97 (s,1H), 1.66 (s, 6H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −124.52. Mass spectrum(ESI, m/z): Calculated for C₂₂H₁₇FN₂O₄, 393.1 (M+H), found 393.1.

Example 21 Compound #15-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation on(E)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropylidene)oxazolidine-2,4-dionefollowed by demethylation of5-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)oxazolidine-2,4-dionewith TMSCl/NaI to yield the product as a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.43 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.88(d, J=8.8 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H),7.52-7.58 (m, 1H), 7.28-7.32 (m, 1H), 6.75 (d, J=7.2 Hz, 1H), 4.57 (d,J=8.8 Hz, 1H), 2.66-2.70 (m, 1H), 2.32-2.36 (m, 1H), 1.50 (s, 6H). ¹⁹FNMR (400 MHz, CD₃OD) δ: −124.54. Mass spectrum (ESI, m/z): Calculatedfor C₂₂H₁₉FN₂O₄, 395.1 (M+H), found 395.0.

Example 22 Compound #113 and #114(Z)-5-(3-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-methylpentan-2-ylidene)oxazolidine-2,4-dioneand(E)-5-(3-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-methylpentan-2-ylidene)oxazolidine-2,4-dione

Step 1:3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentan-2-ol

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanal(200 mg, 0.593 mmol, 1 equiv.), THF (8 mL). This was followed byaddition of methylmagnesium bromide (1.18 mL, 1.18 mmol, 2 equiv.)dropwise with stirring at 0° C. The reaction was stirred 2 h at 0° C.The reaction progress was monitored by TLC (PE:EA=4:1). The reaction wasthen quenched by the addition of H₂O (20 mL), extracted with ethylacetate and the organic layers combined. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with PE:EA=2:1 to yield3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentan-2-olas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₄FNO₂, 354.2 (M+H), found354.1.

Step 2:3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentan-2-one

Into a 100-mL round-bottom flask purged was3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentan-2-ol(200 mg, 0.566 mmol, 1 equiv), DMP (480 mg, 1.132 mmol, 2 equiv.), DCM(10 mL). The resulting solution was stirred overnight at 25° C. Thereaction was monitored by TLC (PE:EA=6:1). The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with PE:EA=6:1 to yield3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentan-2-oneas light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂FNO₂, 352.2 (M+H), found352.1.

Step 3:(Z)-5-(3-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-methylpentan-2-ylidene)oxazolidine-2,4-dioneand(E)-5-(3-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-methylpentan-2-ylidene)oxazolidine-2,4-dione

The title compounds were prepared according to the procedure asdescribed in Example 5 step 1 by reacting oxazolidine-2,4-dione with3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentan-2-oneby t-BuLi, dehydrating of5-(3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-hydroxy-4-methylpentan-2-yl)oxazolidine-2,4-dione,followed by demethylation of (Z) and(E)-5-(3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentan-2-ylidene)oxazolidine-2,4-dionewith TMSCl/NaI to yield the product as off white solids.

(Z)-5-(3-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-methylpentan-2-ylidene)oxazolidine-2,4-dione.¹H NMR (400 MHz, CD₃OD) δ: 8.43 (s, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.87(d, J=8.8 Hz, 1H), 7.77 (t, J=7.6 Hz, 2H), 7.53-7.59 (m, 1H), 7.28-7.33(m, 1H), 6.86 (d, J=7.6 Hz, 1H), 4.04 (d, J=11.6 Hz, 1H), 2.47-2.54 (m,1H), 2.13 (s,3H), 1.04 (d, J=6.4 Hz, 3H), 1.00 (d, J=7.6 Hz, 3H). ¹⁹FHNMR (400 MHz, CD₃OD) δ: −124.46. Mass spectrum (ESI, m/z): Calculatedfor C₂₄H₂₁FN₂O₄, 421.1 (M+H), found 421.1.

(E)-5-(3-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-methylpentan-2-ylidene)oxazolidine-2,4-dione.1H NMR (400 MHz, CD₃OD) δ: 8.43 (s, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.87(d, J=8.8 Hz, 1H), 7.76-7.79 (m, 2H), 7.53-7.58 (m, 1H), 7.28-7.32 (m,1H), 6.83 (d, J=7.2 Hz, 1H), 5.02 (d, J=11.6 Hz, 1H), 2.54-2.60 (m, 1H),1.85 (s, 3H), 1.01 (d, J=6.4 Hz, 3H), 0.99 (d, J=6.4 Hz, 3H). ¹⁹F NMR(400 MHz, CD₃OD) δ: −124.49. Mass spectrum (ESI, m/z): Calculated forC₂₄H₂₁FN₂O₄, 421.1 (M+H), found 421.1.

Example 23 Compound #945-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)-oxazolidine-2,4-dione

Step 1: 1-(6-chloro-2-methoxypyridin-3-yl)-2-methylpropan-1-one

A 250 mL flask was charged with a solution of 2-chloro-6-methoxypyridine(20 g, 0.139 mol, 1 equiv.) in THF (300 mL) under nitrogen atmosphere.To the mixture was then added tert-butyllithium (131 mL, 0.210 mol, 1.5equiv.), which was added dropwise with stirring at −70° C. The reactionmixture was stirred at −78° C. for 2 h. N-methoxy-N-methylisobutyramide(24 g, 0.182 mol, 1.3 equiv.) was then added dropwise. The mixture wasstirred for 3.0 h at −78° C. The reaction progress was monitored byLCMS. The reaction was quenched by the addition of ammonium chlorideaqueous solution and then extracted with ethyl acetate, the organiclayers combined and concentrated under vacuum. The residue was appliedonto a silica gel column with PE/EA=100/1 to yield1-(6-chloro-2-methoxypyridin-3-yl)-2-methylpropan-1-one as yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₀H₁₂ClNO₂, 214.1 (M+H), found214.1.

Step 2:(Z)-6-chloro-2-methoxy-3-(1-methoxy-3-methylbut-1-en-2-yl)pyridine

Into a 500 ml round-bottom flask were placed (Methoxymethyl)triphenylphosphonium chloride (20.5 g, 59.802 mmol, 1.3 eq.) and THF(200 ml) under an atmosphere of nitrogen. The mixture was stirred at 0°C. LiHMDS (61 mL) was added dropwise in 30 min. The reaction mixture wasstirred for 1 h at 0° C. A solution of1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-one(10 g, 46.803 mmol, 1.0 eq.) in THF was added dropwise in 30 min. Themixture was stirred overnight at 0° C. The mixture was quenched by waterand concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:15) to yield(Z)-6-chloro-2-methoxy-3-(1-methoxy-3-methylbut-1-en-2-yl)pyridine asyellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₂H₁₆ClNO₂, 242.1 (M+H), found242.1.

Step 3: 2-(6-chloro-2-methoxypyridin-3-yl)-3-methylbutanal

To a solution of4-chloro-2-methoxy-1-(1-methoxy-3-methylbut-1-en-2-yl)benzene (11.7 g,38.882 mmol, 1.0 eq.) in THF (150 mL). Hydrochloric acid (4 mL) wasadded. The mixture was stirred overnight at room temperature. Themixture was monitored by LCMS. The mixture was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (15/1) to yield2-(6-chloro-2-methoxypyridin-3-yl)-3-methylbutanal as yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₀H₁₆FNO₂, 228.1 (M+H), found227.8.

Step 4: 6-bromo-1-ethyl-4-fluoro-1H-indazole

Into a 25 ml round-bottom flask were placed a solution of6-bromo-4-fluoro-1H-indazole (500 mg, 2.325 mmol, 1 equiv.) in DMF.Potassium carbonate (355 mg, 2.569 mmol, 1.1 equiv.), and iodoethane(474 mg, 3.039 mmol, 1.5 equiv.) were added. The reaction mixture wasstirred for 15 min, and then the mixture was stirred for 1 h at 70° C.The reaction was monitored by LCMS. The mixture was concentrated undervacuum. The residue was purified by chromatogram on silica gel withethyl acetate/petroleum ether (1:6) to yield6-bromo-1-ethyl-4-fluoro-1H-indazole as brown oil and 210 mg6-bromo-2-ethyl-4-fluoro-2H-indazole as brown solid.

Mass spectrum (ESI, m/z): Calculated for C₉H₈BrFN₂, 243.0 (M+H), found242.9.

Step 5:1-ethyl-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

Into a 100 ml round-bottom flask were placed a solution of6-bromo-1-ethyl-4-fluoro-1H-indazole (1.1 g, 4.525 mmol, 1 equiv.) inDMF (15 mL), and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.78 g,7.010 mmol, 1.5 equiv.), potassium acetate (1.6 g, 16.303 mmol, 3.5equiv.), Pd(dppf)Cl₂ (114 mg, 0.140 mmol, 0.03 equiv.) were added. Themixture was stirred overnight at 90° C. under nitrogen atmosphere. Thereaction was monitored by LCMS. The mixture was extracted with ethylacetate (3×30 mL). The organic layers were combined, washed with sodiumcarbonate (aq.) and brine, dried and concentrated under vacuum. Theresidue was purified by thin layer chromatography developed with PE/EA(6/1) to yield a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₅H₂₀BFN₂O₂, 291.2 (M+H),found 291.1.

Step 6.2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutanal

Into a 50 mL round-bottom flask were placed2-(6-chloro-2-methoxypyridin-3-yl)-3-methylbutanal (300 mg, 1.318 mmol,1 equiv.) in ethylene glycol dimethyl ether (20 ml), and then1-ethyl-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(422 mg, 1.454 mmol, 1.3 equiv.), sodiumcarbonate (280 mg, 2.642 mmol, 2equiv.), and water (1 mL) were added. Pd(dppf)Cl₂.CH₂Cl₂ (33 mg, 0.040mmol, 0.03 equiv.) was then added. The flask was evacuated and flushedthree times with nitrogen. The mixture was stirred overnight at 90° C.under an atmosphere of nitrogen (balloon). The reaction was monitored byLCMS. The resulting solution was distilled in H₂O, extracted with ethylacetate (3×30 mL). The organic layers were combined and washed withsodium chloride (aq.) dried and concentrated under vacuum. The residuewas applied on a silica gel column and eluted with PE/EA (6/1) to yielda yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₀H₂₂FN₃O₂, 356.2 (M+H), found356.1.

Step 7:5-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)-oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 by reacting oxazolidine-2,4-dione with2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutanalby t-BuLi, dehydrating5-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-1-hydroxy-3-methylbutyl)oxazolidine-2,4-dione,followed by demethylation of(Z)-5-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione with TMSCl/NaI toyield the product as an off white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.15 (s, 1H), 7.81 (s, 1H), 7.60 (d, J=7.2Hz, 1H), 7.20 (d, J=10Hz, 1H), 6.76 (d, J=7.6Hz, 1H), 6.35 (d, J=10.4Hz, 1H), 4.51-4.60 (m, 2H), 3.70-3.80 (t, J=9.8 Hz, 1H), 2.31-2.40 (m,1H), 1.53-1.57 (t, J=7.2Hz, 3H), 1.02 (d, J=6.8 Hz, 3H), 0.94 (d,J=6.8Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −119.17. Mass spectrum (ESI,m/z): Calculated for C₂₂H₂₁FN₄O₄, 425.2 (M+H), found 425.2.

Example 24 Compound #116(Z)-5-(2-(6-(4-chloro-1-ethyl-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with 6-bromo-4-chloro-1H-indazole, reactingoxazolidine-2,4-dione with2-(6-(1-ethyl-4-chloro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutanalby t-BuLi, dehydrating5-(2-(6-(1-ethyl-4-chloro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-1-hydroxy-3-methylbutyl)oxazolidine-2,4-dione, followed by demethylation of(Z)-5-(2-(6-(1-ethyl-4-chloro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dionewith TMSCl/NaI to yield the product as a yellow solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.14 (s, 1 H), 7.92 (s, 1 H), 7.61 (d, J=7.2Hz, 1 H), 7.51 (s, 1 H), 6.76 (d, J=7.6 Hz, 1 H), 6.39 (d, J=10.4 Hz, 1H), 4.53-4.58 (m, 2 H), 3.71-3.76 (m, 1 H), 2.33-2.39 (m, 1 H), 1.53 (t,J=7.2 Hz, 3 H), 1.02 (d, J=6.8 Hz, 3 H), 0.93 (d, J=6.4 Hz, 3 H). Massspectrum (EI, m/z): Calculated for C₂₂H₂₂C₁₂N₄O₄, 441.1 (M−HCl+H), found441.1.

Example 25 Compound #106(Z)-5-(2-(6-(1-ethyl-4-methyl-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with 6-bromo-4-methyl-1H-indazole, reactingoxazolidine-2,4-dione with2-(6-(1-ethyl-4-methyl-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutanalby t-BuLi, dehydrating5-(2-(6-(1-ethyl-4-methyl-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-1-hydroxy-3-methylbutyl)oxazolidine-2,4-dione, followed by demethylation of(Z)-5-(2-(6-(1-ethyl-4-methyl-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dionewith TMSCl/NaI to yield the product as a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.38 (s, 1 H), 7.74 (d, J=7.4 Hz, 1 H), 7.56(d, J=7.2 Hz, 1 H), 7.12 (d, J=7.6 Hz, 1 H), 6.66 (d, J=7.2 Hz, 1 H),6.37 (d, J=10.8 Hz, 1 H), 4.49-4.54 (m, 2 H), 3.70-3.73 (m, 1 H), 2.60(s, 3 H), 2.29-2.40 (m, 1 H), 1.59-1.63 (m, 3 H), 1.16 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.4 Hz, 3 H). Mass spectrum (EI, m/z): Calculated forC₂₃H₂₄N₄O₄, 421.2 (M+H), found 421.0.

Example 26 Compound #98(Z)-5-(2-(6-(2-ethyl-4-methyl-2H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with 6-bromo-2-ethyl-4-methyl-2H-indazole,reacting oxazolidine-2,4-dione with2-(6-(2-ethyl-4-methyl-2H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutanalby t-BuLi, dehydrating5-(2-(6-(2-ethyl-4-methyl-2H-indazol-6-yl)-2-methoxypyridin-3-yl)-1-hydroxy-3-methylbutyl)oxazolidine-2,4-dione,followed by demethylation of(Z)-5-(2-(6-(2-ethyl-4-methyl-2H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dionewith TMSCl/NaI to yield the product as a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.11 (s, 1 H), 7.72 (s, 1 H), 7.57 (d, J=7.2Hz, 1 H), 7.23 (s, 1 H), 6.70 (d, J=7.2 Hz, 1 H), 6.32 (d, J=10.4 Hz, 1H), 4.48-4.53 (m, 2 H), 3.71 (t, J=7.2 Hz, 1 H), 2.65 (s, 3 H),2.28-2.38 (m, 1 H), 1.49 (t, J=7.2 Hz, 3 H), 1.00 (d, J=6.4 Hz, 3 H),0.92 (d, J=6.8 Hz, 3 H).

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₄N₄O₄, 421.2 (M+H), found421.2.

Example 27 Compound #97(Z)-5-(2-(6-(7-chloro-1-methyl-1H-benzo[d]imidazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Step 1: 5-bromo-7-chloro-1H-benzo[d]imidazole

5-bromo-7-chloro-1H-benzimidazole A solution of5-bromo-3-chlorobenzene-1,2-diamine (2 g, 9.03 mmol) in formic acid (30ml) was heated at reflux for 16 hours. The reaction progress wasmonitored by LCMS. Reaction mixture was concentrated under vacuum toyield brown oil. The mixture was extracted by EtOAc from a saturatedaqueous solution of NaHCO₃, dried over MgSO₄ and evaporated under vacuumto yield 5-bromo-7-chloro-1H-benzo[d]imidazole as a pale yellow solid.

Mass spectrum (EI, m/z): Calculated for C₇H₄BrClN₂, 232.5 (M+H), found233.0.

Step 2: 5-bromo-7-chloro-1-methyl-1H-benzo[d]imidazole

Into a 100-mL round-bottom flask, were placed5-bromo-7-chloro-1H-1,3-benzodiazole (1 g, 4.320 mmol, 1.00 equiv), THF(40 mL). To the mixture was then added NaH (60%) (0.52 g) in portions at0° C. The resulting solution was stirred for 1 h at 0° C. To this wasthen added MeI (1 mL). The resulting solution was stirred for 2 h at 25°C. The reaction progress was monitored by LCMS. The reaction was thenquenched by the addition of water (10 mL). The resulting solution wasextracted with ethyl acetate (3×30 mL) and the organic layers combinedand concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1/20) to yield5-bromo-7-chloro-1-methyl-1H-benzo[d]imidazole as yellow solid.

Mass spectrum (EI, m/z): Calculated for C₈H₆BrClN₂, 246.5 (M+H), found246.9.

Step 3:(Z)-5-(2-(6-(7-chloro-1-methyl-1H-benzo[d]imidazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as ayellow solid.

¹H NMR (300 MHz, CD₃OD) δ: δ 8.61 (s, 1 H), 8.00 (s, 1 H), 7.78 (s, 1H), 7.61 (d, J=7.3 Hz, 1 H), 6.76 (d, J=7.4 Hz, 1 H), 6.39 (d, J=10.6Hz, 1 H), 4.05 (s, 3 H), 3.68-3.78 (m, 1 H), 2.27-2.45 (m, 1 H), 1.03(d, J=6.7 Hz, 3 H), 0.94 (d, J=6.7 Hz, 3 H). Mass spectrum (EI, m/z):Calculated for C₂₁H₁₉ClN₄O₄, 427.1 (M+H), found 426.9.

Example 28 Compound #118(Z)-5-(3-methyl-2-(6-(1-methyl-1H-indol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as whitesolid.

¹H NMR (400 MHz, CD₃OD) δ: 7.92 (s, 1H), 7.57 (d, J=7.6 Hz, 1H),7.47-7.55 (m, 2H), 7.28 (d, J=3.2 Hz, 1H), 6.65 (d, J=7.2 Hz, 1H), 6.57(d, J=3.2 Hz, 2H), 6.35 (d, J=10.8 Hz, 1H), 3.87 (s, 3H), 2.32-2.40 (m,3H), 1.02 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H). Mass spectrum (ESI,m/z): Calculated for C₂₂H₂₁N₃O₄, 392.2 (M+H), found 392.2.

Example 29 Compound #93(Z)-5-(2-(6-(benzo[d]isothiazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as yellowsolid.

¹H NMR (300 MHz, CD₃OD) δ: 8.94 (s, 1H), 8.31 (s, 1H), 8.18 (d, J=7.8Hz, 1H), 7.68 (d, J=9.9 Hz, 1H), 7.50 (d, J=7.5 Hz, 1H), 6.65 (d, J=6.9Hz, 1H), 6.27 (d, J=10.5 Hz, 1H) 3.59-3.65 (m, 1H),2.24-2.31 (m, 1H),0.91 (d, J=6.6 Hz, 3H), 0.82 (d, J=6.6 Hz, 3H). Mass spectrum (ESI,m/z): Calculated for C₂₁H₂₁N₃O₅S, 396.1 (M+H), found 396.0.

Example 30 Compound #274 and #275(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-2,3-dihydropyridin-3-yl)-3,3-dimethylbutylidene)oxazolidine-2,4-dioneand(E)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-2,3-dihydropyridin-3-yl)-3,3-dimethylbutylidene)oxazolidine-2,4-dione

Step 1: Ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-hydroxy-3,3-dimethylbutanoate

Into a 100-mL round bottle maintained with an inert atmosphere ofnitrogen, to a solution of tert-butylmagnesium chloride (5 mL, 5.000mmol, 2.00 equiv.) in THF (20 mL), add ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-oxoacetate (900mg, 2.500 mmol, 1.00 equiv.) with stirring at 0° C. The resultingsolution was stirred 16 h at 20° C. The reaction was concentrated undervacuum. The residue product was purified by chromatogram on silica gelwith ethyl acetate/petroleum ether (7:93) to yield ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-hydroxy-3,3-dimethylbutanoateas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₆FNO₄, 412.2 [M+H], found412.0.

Step 2:(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3,3-dimethylbutane-1,2-diol

Into a 50-mL round bottle, to a solution of ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-hydroxy-3,3-dimethylbutanoate(320 mg, 0.780 mmol, 1.00 equiv.) in THF (10 mL), was added LAH (88 mg,2.300 mmol, 3.00 equiv). The resulting solution was stirred 6 h at 20°C. The mixture was quenched by the addition of Na₂SO₄.10H₂O, the solidwere filtered out, the organic layers was concentrated under vacuum. Theresidue product was purified by chromatogram on TLC with ethylacetate/petroleum ether (1:3) to yield(S)-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3,3-dimethylbutane-1,2-diolas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₄FNO₃, 370.2 [M+H], found369.9.

Step 3:3-(2-tert-butyloxiran-2-yl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridine

Into a 8-mL vial maintained with an inert atmosphere of nitrogen, wereplaced(S)-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3,3-dimethylbutane-1,2-diol(170 mg, 0.500 mmol, 1.00 equiv.), toluene (10 mL), PPh₃ (242 mg, 0.920mmol, 2.00 equiv.). DEAD (185 mg, 0.920 mmol, 2.00 equiv) was then addedwith stirring at 0° C. The mixture was stirred at 20° C. for 16 h. Themixture was concentrated under vacuum to yield3-(2-tert-butyloxiran-2-yl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridineas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂FNO₂, 352.2 [M+H], found352.3

Step 4:2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3,3-dimethylbutanal

Into a 8-mL vial were placed3-(2-tert-butyloxiran-2-yl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridine(160 mg, 0.400 mmol, 1.00 equiv.), THF (10 mL). BCl₃(0.5 mL, 0.500 mmol,1.10 equiv.) was then added with stirring at 20° C. The mixture wasstirred at 20° C. for 5 h. The mixture was quenched by the addition ofMeOH. The organic layer was concentrated under vacuum. The residue waspurified by TLC with ethyl acetate/petroleum ether (1:6) to yield2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3,3-dimethylbutanalas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂FNO₂, 352.2 [M+H], found351.9.

Step 5:(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-2,3-dihydropyridin-3-yl)-3,3-dimethylbutylidene)oxazolidine-2,4-dioneand(E)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-2,3-dihydropyridin-3-yl)-3,3-dimethylbutylidene)oxazolidine-2,4-dione

The title compounds were prepared according to the procedure asdescribed in Example 5 starting with aldol condensation by t-BuLi,dehydration followed by demethylation with TMSCl/NaI to yield theproduct as yellow solids.

(E)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-2,3-dihydropyridin-3-yl)-3,3-dimethylbutylidene)oxazolidine-2,4-dione. ¹H NMR (300 MHz, CD₃OD) δ: 8.33-8.35(m, 1H), 8.24 (d, J=8.8 Hz, 1H), 7.82 (s, 1H), 7.56-7.69 (m, 2H),7.23-7.32 (m, 1H), 6.69-6.84 (m, 2H), 6.55 (d, J=9.1 Hz, 1H), 4.78-4.82(m, 1H), 0.98 (s, 9H). ¹⁹F NMR (300 MHz, CD₃OD) δ −77.24, −122.85. Massspectrum (ESI, m/z): Calculated for C_(24.9)H_(21.45)F_(2.35)N₂O_(4.9),421.1 [M−0.45CF₃COOH+H], found 421.0.

(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-2,3-dihydropyridin-3-yl)-3,3-dimethylbutylidene)oxazolidine-2,4-dione. ¹H NMR (300 MHz,CD₃OD) δ 8.26-8.33 (m, 2H), 7.82(s, 1H), 7.66-7.71 (m, 1H), 7.53-7.58 (m, 1H), 7.23-7.29 (m, 1H),6.80-6.84 (m, 2H), 6.55 (d, J=9.0 Hz, 1H), 5.74 (d, J=12.1 Hz, 1H), 1.00(s, 9H). ¹⁹F NMR (300 MHz, CD₃OD) δ −77.21, −123.27. Mass spectrum (ESI,m/z): Calculated for C_(27.6)H₂₂.F_(6.4)N₂O_(7.6), 421.1[M−1.80CF₃COOH+H], found 421.2.

Example 31 Compound #123(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-2,3-dihydropyridin-3-yl)-2-phenylethylidene)oxazolidine-2,4-dione

Step 1: (6-chloro-2-methoxypyridin-3-yl)(phenyl)methanone

To 2-chloro-6-methoxypyridine (1 g, 6.965 mmol 1 equiv.) in THF (50 mL)under N₂ atmosphere at −78° C. was added t-BuLi (6.5 mL, 1.5 equiv.)dropwise. The reaction mixture was stirred at −78° C. for 3 h, thenN-methoxy-N-methylbenzamide (1.28 g, 7.749 mmol 1.1 equiv.) was added.The reaction was stirred at −78° C. for 3 h. The reaction was monitoredby TLC (PE/EA=15/1). The reaction was quenched by NH₄Cl and the mixturewas extracted with EtOAc (3×50 mL). The resulting mixture was evaporatedunder reduced pressure to yield (6-chloro-2-methoxypyridin-3-yl)(phenyl)methanone as a yellow oil.

¹H NMR (400 MHz, CD₃OD, ppm) δ: 7.76-7.85 (m, 2 H), 7.72 (d, J=7.7 Hz, 1H), 7.57-7.67 (m, 1 H), 7.48 (t, J=7.7 Hz, 2 H), 7.06 (d, J=7.7 Hz, 1H), 3.91 (s, 3H).

Step 2: (E)-6-chloro-2-methoxy-3-(2-methoxy-1-phenylvinyl)pyridine

Into a 250-mL round-bottom flask, were placed (methoxymethyl)triphenylphosphonium chloride (4 g, 11.669 mmol, 2.064 equiv.), in THF(70 mL). To the mixture was then added LIHMDS (15 ml), in portions at 0°C. The resulting solution was stirred for 1 h at 0° C. To the mixturewas added (6-chloro-2-methoxypyridin-3-yl) (phenyl) methanone (1.4 g).The resulting solution was stirred for 16 h at 25° C. The reactionprogress was monitored by TLC (PE/EA=15/1). The resulting solution wasquenched by H₂O (20 mL). The mixture was extracted with EtOAc (3×50 mL),the organic layers combined and concentrated under vacuum. The residuewas applied onto a silica gel column with PE/EA (95/5) to(E)-6-chloro-2-methoxy-3-(2-methoxy-1-phenylvinyl) pyridine as yellowoil.

Mass spectrum (EI, m/z): Calculated For C₁₅H₁₄ClNO₂, 275.7 [M+H]⁺, found275.9.

Step 3: 2-(6-chloro-2-methoxypyridin-3-yl)-2-phenylacetaldehyde

To (Z)-6-chloro-2-methoxy-3-(2-methoxy-1-phenylvinyl) pyridine (800 mg,2.901 mmol 1 equiv.) in CH₃CN (50 mL) was added HBr (1 mL). The reactionmixture was stirred at room temperature for 2 h. The reaction wasmonitored by TLC (PE/EA=6/1). The reaction was quenched by H₂O and themixture was extracted with EtOAc (3×30 mL). The organic layers combinedand concentrated under vacuum. The residue was applied onto a silica gelcolumn with PE/EA=(95/5) to yield2-(6-chloro-2-methoxypyridin-3-yl)-2-phenylacetaldehyde as yellow oil.

Mass spectrum (EI, m/z): Calculated For C₁₄H₁₂ClNO₂, 261.7 [M+H]⁺, found262.1.

Step 4:2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-phenylacetaldehyde

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed a solution of2-(6-chloro-2-methoxypyridin-3-yl)-2-phenylacetaldehyde (800 mg, 3.068mmol, 1.0 equiv.) in DME/H₂O (50 mL).2-(8-Fluoronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.25 g, 4.594 mol, 1.5 equiv.), Pd(dppf)Cl₂.CH₂Cl₂ (75 mg, 0.092 mmol,0.03 equiv.), Na₂CO₃ (1.14 mg, 10.755 mmol, 3.5 equiv.) were then added.The resulting solution was stirred overnight at 90° C. in an oil bath.The reaction was monitored by TLC (PE/EA=15/1). The resulting solutionwas quenched by water (25 mL). The mixture was then extracted with EtOAc(3×50 mL), and the organic layers combined and concentrated undervacuum. The residue was applied onto a silica gel column with PE/EA(95/5) to yield2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-phenylacetaldehydeas a yellow oil.

Mass spectrum (EI, m/z): Calculated For C₂₄H₁₈FNO₂,371.4 [M+H]⁺, found372.1.

Step 5:(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-2,3-dihydropyridin-3-yl)-2-phenylethylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (400 MHz, Methanol-d₄, ppm) 58.43 (s, 1 H), 8.04-8.11 (m, 1 H),7.87 (d, J=8.7, 1.9 Hz, 1 H), 7.78 (d, J=8.3 Hz, 1 H), 7.65 (d, J=7.3Hz, 1 H), 7.56 (d, J=8.0 Hz, 1 H), 7.35-7.43 (m, 4 H), 7.24-7.34 (m, 2H), 6.81 (d, J=7.2 Hz, 1 H), 6.45 (s, 1 H), 5.41 (d, J=10.2 Hz, 1 H),¹⁹F NMR (400 MHz, Methanol-d₄, ppm) δ: −124.442. Mass spectrum (EI,m/z): Calculated For C₂₆H₁₇FN₂O₄, 440.4 [M+H]⁺, found 441.2.

Example 32 Compound #117(E)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-phenylpropylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as anoff-white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.38 (s, 1 H), 8.04 (d, J=8.8 Hz, 1H), 7.82(d, J=7.2 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.49-7.56 (m, 2 H), 7.21-7.30(m, 5 H), 7.14-7.17 (m, 1 H), 6.69 (d, J=7.2 Hz,1H), 6.36 (d, J=10.0Hz,1H), 4.25-4.31 (m, 1 H), 3.17-3.30 (m, 1 H), 3.01-3.15 (m, 1 H). ¹⁹FNMR (400 MHz, CD₃OD) δ: −124.45. Mass spectrum (EI, m/z): Calculated forC₂₇H₁₉FN₂O₄, 455.1 (M+H), found 455.2.

Example 33 Compound #1055-(3-ethyl-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)pentylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (400 MHz,CD₃OD) δ: 8.44 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.84 (d,J=8.8 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.51-7.56(m, 1H), 7.26-7.28 (m, 1H), 6.76-6.80 (m, 1H), 6.33 (d, J=5.2 Hz, 1H),4.01 (t, J=10 Hz, 1H), 2.11 (s, 1H), 1.54-1.56 (m, 1H), 1.33-1.42 (m,3H), 0.89-0.93 (m, 6H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −124.47. Massspectrum (ESI, m/z): Calculated For C₂₅H₂₃FN₂O₄, 435.2 (M+H), found435.2.

Example 34 Compound #103(Z)-5-(2-cyclopropyl-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)ethylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (400 MHz, Methanol-d₄) δ 8.43 (s, 1 H), 8.05-8.12 (d, J=11.2 Hz,1 H), 7.85-7.88 (m, 1 H), 7.76-7.79 (m, 2 H), 7.54-7.59 (m, 1 H),7.26-7.36 (m, 1 H), 6.82 (d, J=7.2 Hz, 1 H), 6.31 (d, J=9.9 Hz, 1 H),3.27 (t, J=9.7 Hz, 1 H), 1.48-1.52 (m, 1 H), 0.56-0.71 (m, 2 H),0.38-0.46 (m, 1 H), 0.27-0.37 (m, 1 H). ¹⁹F NMR (400 MHz, Methanol-d₄)δ: −124.477. Mass spectrum (EI, m/z): Calculated for C₂₃H₁₇FN₂O₄, 405.1(M+H), found 405.0.

Example 35 Compound #92(Z)-5-(2-cyclopentyl-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)ethylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ: 8.40 (s, 1 H), 8.07 (d, J=8.2 Hz, 1 H), 7.85(m, 1 H), 7.72 (m, 2 H), 7.50 (m, 1 H), 7.31 (m, 1 H), 6.80 (d, J=7.5Hz, 1 H), 6.28 (d, J=6.9 Hz, 1 H), 3.70 (m, 1H), 2.55 (m, 1H), 1.69 (m,6H), 1.28 (m, 2H). Mass spectrum (EI, m/z): Calculated for C₂₅H₂₁FN₂O₄,433.45 [M+H], found 433.6.

Example 36 Compound #134(Z)-5-(2-cyclohexyl-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)ethylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ: 8.40 (s, 1 H), 8.07 (d, J=8.2 Hz, 1 H), 7.85(m, 1 H), 7.72 (m, 2 H), 7.50 (m, 1 H), 7.31 (m, 1 H), 6.80 (d, J=7.5Hz, 1 H), 6.28 (d, J=6.9 Hz, 1 H), 3.65 (m, 1H), 2.01 (m, 1H), 1.68 (m,4H), 1.15 (m, 4H), 0.95 (m, 2H). Mass spectrum (EI, m/z): Calculated forC₂₆H₂₃FN₂O₄, 447.48 [M+H], found 447.8.

Example 37 Compound #875-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)oxazoli-dine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation of 5(Z)-5-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dionefollowed by demethylation of5-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dionewith TMSCl/NaI in CH₃CN to yield the product as a light yellow solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.14 (s, 1H), 7.82 (s, 1H), 7.49-7.54 (t,J=6.75 Hz, 1H), 7.21 (d, J=11.1 Hz, 1H), 6.71-6.78 (m, 1H), 4.68-4.72(m, 1H), 4.52-4.60 (m, 2H), 2.89-2.98 (m, 1H), 2.08-2.65 (m, 3H),1.51-1.57 (t, J=3.6 Hz, 3H), 1.01-1.05 (t, J=6.75 Hz, 3H), 0.83-0.90 (m,1H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −119.22. Mass spectrum (ESI, m/z):Calculated for C₂₂H₂₃FN₄O₄, 427.2 (M+H), found 427.1.

Example 38 Compound #110 and #1205-(2-(6-(4-chloro-2-ethyl-2H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dioneand5-(2-(6-(2-ethyl-2H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dione

The title compounds were prepared according to the procedure asdescribed in Example 8 step 1 by hydrogenation followed by demethylationto yield the products.

5-(2-(6-(4-chloro-1-ethyl-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dioneas a white solid. ¹H NMR(300 MHz, CD₃OD) δ: 8.25 (s, 1H), 7.83 (s, 1H),7.55 (d, J=7.2 Hz, 1H), 7.43 (s, 1H), 6.74 (d, J=7.2 Hz, 1H), 4.84-4.89(m, 1H), 4.49-4.52 (m, 2H), 2.80-2.92 (m, 1H), 2.40-2.42 (m, 2H),1.95-2.09 (m, 1H), 1.50 (t, J=7.2 Hz, 3H), 1.06 (d, J=7.2 Hz, 3H), 0.90(d, J=6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₂H₂₃ClN₄O₄, 443.1 [M+H], found 442.9.

and5-(2-(6-(1-ethyl-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dioneas a white solid. ¹H NMR(300 MHz, CD₃OD) δ: 8.24 (s, 1 H), 7.73 (d,J=8.7 Hz, 1H), 7.52-7.58 (m, 2H), 7.41 (d, J=7.2 Hz, 1H), 6.74-6.76 (m,1H), 4.74-4.78 (m, 1H), 4.50-4.57 (m, 2H), 2.80-2.92 (m, 1H), 2.32-2.68(m, 1H), 2.15-2.17 (m, 2H), 1.50 (t, J=7.2 Hz, 3H), 1.03 (d, J=6.6 Hz,3H), 0.90 (d, J=6.6 Hz, 3H). Mass spectrum (EI, m/z): Calculated forC₂₂H₂₄N₄O₄, 409.2 [M+H], found 408.9.

Example 39 Compound #1265-(2-(6-(1-ethyl-4-methyl-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation followed by demethylation to yieldan off-white solid.

¹H NMR(400 MHz, CD₃OD) δ: 8.13 (s, 1 H), 7.73 (s, 1 H), 7.50 (t, J=6.8Hz, 1 H), 7.24 (s, 1 H), 6.67-6.72 (m, 1 H), 4.67-4.70 (m, 1 H),4.48-4.53 (m, 2 H), 2.88-2.91 (m, 1 H), 2.65 (s, 3 H), 2.39-2.52 (m, 1H), 2.07-2.38 (m, 2 H), 1.50 (t, J=7.2 Hz, 3 H), 1.02 (t, J=6.8 Hz, 3H), 0.87 (t, J=6.4 Hz, 3 H). Mass spectrum (EI, m/z): Calculated forC₂₃H₂₆N₄O₄, 423.2 (M+H), found 423.0.

Example 40 Compound #865-(2-(6-(2-ethyl-4-methyl-2H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation followed by demethylation to yielda white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.11 (s, 1H), 7.73 (s, 1H), 7.48 (t, J=8.8Hz, 1H), 7.23 (s, 1H), 6.67-6.72 (m, 1 H), 4.65-4.68 (m, 1 H), 4.48-4.58(m, 2 H), 2.87-2.95 (m, 1H), 2.65 (s, 3H), 2.39-2.51 (m, 1 H), 2.08-2.13(m, 2 H), 1.47-1.51 (m, 3 H), 0.98-1.01 (m, 3 H), 0.85-0.92 (m, 3 H).Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₆N₄O₄, 423.2 (M+H), found423.0.

Example 41 Compound #1075-(2-(6-(7-chloro-1-methyl-1H-benzo[d]imidazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation followed by demethylation to yielda white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.32 (s, 1 H), 7.92 (s, 1H), 7.70 (s,1H),7.49-7.53 (m,1H), 6.69-6.74 (m, 1 H), 4.83-4.89 (m, 1 H), 4.00 (s, 3 H),2.90-3.14 (m,1H), 2.40-2.44 (m,1H), 2.10-2.19 (m, 2 H), 1.01-1.31 (m, 3H), 0.87-0.92 (m, 3 H). Mass spectrum (ESI, m/z): Calculated ForC₂₁H₂₁ClN₄O₄, 429.1 (M+H), found 429.0.

Example 42 Compound #1305-(2-cyclopentyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)ethylidene)-oxazolidine-2,4-dione

Step 1: Ethyl2-(6-chloro-2-methoxypyridin-3-yl)-2-cyclopentyl-2-hydroxyacetate

Into a 8 mL tube were placed a solution of 2-chloro-6-methoxypyridine(400 mg, 2.786 mmol, 1.00 equiv.) in THF (10 mL) under an atmosphere ofnitrogen. The suspension was stirred at −78° C. and n-BuLi (2 ml, 4.197mmol, 1.50 equiv.) was added dropwise in 15 min. The mixture was stirredfor 1.5 h. The mixture was then cooled to −78° C. A solution of ethyl2-cyclopentyl-2-oxoacetate (711 mg, 4.197 mmol, 1.50 equiv.) in THF (10mL) was added dropwise in 15 min. The mixture was stirred for another1.5 h. The reaction was monitored by LCMS. The mixture was quenched withwater and extracted with EtOAc. The organic layer was washed with brineand concentrated under vacuum. The residue was applied onto silica gelcolumn with PE/EA (5/1) to yield ethyl2-(6-chloro-2-methoxypyridin-3-yl)-2-cyclopentyl-2-hydroxyacetate.

Mass spectrum (ESI, m/z): Calculated for C₁₅H₂₀ClNO₄, 314.1[M+H], found313.8.

Step 2: Ethyl2-(6-chloro-2-methoxypyridin-3-yl)-2-cyclopentylideneacetate

Into a 100 ml round-bottom flask were placed a solution of ethyl2-(6-chloro-2-methoxypyridin-3-yl)-2-cyclopentyl-2-hydroxyacetate (200mg, 0.637 mmol, 1.00 equiv.) and 4-methylbenzenesulfonic acid (1.097 g,6.37 mmol, 10.00 equiv.) in toluene (50 mL). The mixture was stirred for2 h at 120° C. The water formed in the reaction was removed via aDean-Stark tube. The reaction was monitored by LCMS. The mixture waswashed with brine. The organic layer was concentrated under vacuum. Theresidue was applied onto a silica gel column and eluted with PE/EA=10/1to yield ethyl2-(6-chloro-2-methoxypyridin-3-yl)-2-cyclopentylideneacetate as yellowoil.

Mass spectrum (ESI, m/z): Calculated for C₁₅H₁₅ClNO₃, 296.1 [M+H], found295.7.

Step 3: Ethyl2-cyclopentylidene-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)acetate

Into a 50 mL round-bottom flask were placed ethyl2-(6-chloro-2-methoxypyridin-3-yl)-2-cyclopentylideneacetate (60 mg,0.204 mmol, 1.00 equiv.) in ethylene glycol dimethyl ether (20 ml), andthen1-ethyl-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(77 mg, 0.265 mmol, 1.30 equiv.), sodium carbonate (43 mg, 0.410 mmol,2.00 equiv.), and water (2 mL) were added. Pd(dppf)Cl₂.CH₂Cl₂ (5 mg,0.006 mmol, 0.03 equiv.) was then added. The flask was evacuated andflushed three times with nitrogen.

The mixture was stirred overnight at 90° C. under an atmosphere ofnitrogen (balloon). The reaction was monitored by LCMS. The resultingsolution was poured into H₂O, extracted with ethyl acetate (3×30 mL).The organic layers were combined and washed with sodium chloride (aq.),dried and concentrated under vacuum. The residue was applied on a silicagel column and eluted with PE/EA (6/1) to yield ethyl2-cyclopentylidene-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)acetateas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₆FN₃O₃, 424.2 [M+H], found423.9.

Step 4: Ethyl2-cyclopentyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)acetate

Into a 25 ml round-bottom flask were placed a solution of ethyl2-cyclopentylidene-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)acetate(40 mg, 0.094 mmol, 1.00 equiv.) in EA (5 mL), then Palladium onactivated carbon (10 mg) was added. The flask was evacuated and flushedthree times with H₂. The mixture was stirred overnight at roomtemperature under an atmosphere of hydrogen. Palladium on activatedcarbon was filtered out. The filtrate was concentrated under vacuum. Theresidue was applied on a silica gel column and eluted with DCM/MeOH(20/1) to yield ethyl2-cyclopentyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)acetateas colorless oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₈FN₃O₃, 246.2 [M+H], found246.0.

Step 5:5-(2-cyclopentyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)ethylidene)-oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as whitesolid.

¹H NMR (300 MHz, CD₃OD) δ: 8.15 (s, 1H), 7.81 (s, 1H), 7.64 (d, J=7.2Hz, 1H), 7.20 (d, J=11.1 Hz, 1H), 6.76 (d, J=7.2 Hz, 1H), 6.20-6.33 (m,1H), 4.48-4.60 (m, 2H), 3.72-3.85 (m, 1H), 2.50-2.70 (m, 1H), 1.60-1.89(m, 6H), 1.51-1.56 (m, 3H), 1.15-1.42 (m, 2H). ¹⁹F NMR (300 MHz, CD₃OD)δ: −119.170. Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₃FN₄O₄, 451.2[M+H], found 451.2.

Example 43 Compound #1275-(2-cyclohexyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)ethylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a lightyellow solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.12 (s, 1H), 7.78 (s, 1H), 7.56 (d, J=7.2Hz, 1H), 7.18 (m, 1H), 6.72 (d, J=7.2 Hz, 1H), 6.32 (d, J=10.8 Hz, 1H),4.40-4.55 (m, 2H), 3.69-3.80 (m, 1H), 1.90-2.10 (m, 1H), 1.55-1.9 (m,4H), 1.42-1.50 (m, 3H), 1.15-1.30 (m, 4H), 0.90-1.01 (m, 2H). ¹⁹F NMR(400 MHz, CD₃OD) δ: −119.174. Mass spectrum (EI, m/z): Calculated forC₂₅H₂₅FN₄O₄, 465.2 [M+H], found 465.1.

Example 44 Compound #122(Z)-5-(2-(6-(4-fluoro-1-isopropyl-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Step 1: 6-bromo-4-fluoro-1-isopropyl-1H-indazole

Into a 25-mL round-bottom flask, were placed a solution of6-bromo-4-fluoro-1H-indazole (50 mg, 0.233 mmol, 1.00 equiv.) andpotassium carbonate (44.993 mg, 0.326 mmol, 1.40 equiv.) in DMF (5 ml),then 2-iodopropane (51.388 mg, 0.302 mmol, 1.30 equiv.) was added. Theresulting solution was stirred for 15 minutes at room temperature thenstirred overnight at 80° C. The reaction was monitored by LCMS. Themixture was extracted with EtOAc, and the combined organic layer. Theorganic layer was evaporated under reduced pressure. The residue waspurified by column chromatography (PE:EA=3:1) to yield6-bromo-4-fluoro-1-isopropyl-1H-indazole as a yellow oil.

Mass spectrum (EI, m/z): Calculated For C₁₀H₁₀BrFN₂, 257.0 [M+H]⁺, found258.9.

Step 2:4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed a solution of6-bromo-4-fluoro-1-isopropyl-1H-indazole (250 mg, 0.972 mmol, 1.00equiv.), bis(pinacolato) diboron (370.387 mg, 1.459 mmol, 1.50 equiv.),Pd(dppf)Cl₂.CH₂Cl₂ (23.822 mg, 0.029 mmol, 0.03 equiv.), potassiumacetate (334.010 mg, 3.403 mmol, 3.5 equiv.) in DMF (8 mL). Theresulting solution was stirred overnight at 90° C. The reaction wasmonitored by LCMS. The resulting solution was extracted with EtOAc, andthe organic layers combined and concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1:3) to yield4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazoleas a green oil.

Mass spectrum (EI, m/z): Calculated For C₁₆H₂₂BFN₂O₂, 305.2 [M+H]⁺,found 305.1.

Step 3:(Z)-5-(2-(6-(4-fluoro-1-isopropyl-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (300 MHz, CD₃OD, ppm) δ: 8.13 (s, 1 H), 7.80 (s, 1 H), 7.57 (d,J=7.2 Hz, 1 H), 7.16 (d, J=11.1 Hz, 1 H), 6.73 (d, J=7.2 Hz, 1 H), 6.34(d, J=10.5 Hz, 1 H), 5.03-5.07 (m, 1 H), 3.67-3.74 (m, 1 H), 2.21-2.57(m, 1 H), 1.58 (d, J=6.6 Hz, 6 H), 1.00 (d, J=8.1 Hz, 3 H), 0.91 (d,J=6.6 Hz, 3 H). ¹⁹F NMR (300 MHz, CD₃OD, ppm) δ: −119.24. Mass spectrum(EI, m/z): Calculated For C₂₃H₂₃FN₄O₄, 439.2 [M+H]⁺, found 439.0.

Example 45 Compound #136(Z)-5-(2-(5-chloro-6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Into a 10-mL sealed tube, were placed(Z)-5-(2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione(30 mg, 0.074 mmol, 1 equiv.), THF (2 mL), CH₃CN (2 mL), TFA (0.4 mL),NCS (9.8 mg, 0.074 mmol, 1 equiv.). The solution was stirred at 40° C.for 6 h. The reaction was then quenched by the addition of MeOH. Theresulting mixture was concentrated under vacuum, and the residuepurified by Prep-HPLC with the following conditions (16#-Waters 2767-5):Column, SunFire Prep C18,19*100 mm, 5 um; mobile phase, Water with 0.05%TFA and CH₃CN (40% CH₃CN up to 80% in 12 min, up to 100% in 0.1 min);Detector, UV 220 & 254 nm to yield(Z)-5-(2-(5-chloro-6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dioneas a white solid.

¹H NMR (300 MHz, CD₃OD, ppm) δ: 8.32 (s, 1 H), 8.06 (d, J=7.2 Hz, 1 H),7.72-7.78 (m, 2H), 7.67 (s, 1H), 7.54-7.59 (m, 1H), 7.27-7.33 (m, 1H),6.38 (d, J=13.5 Hz, 1H), 3.72-3.75 (m, 1H), 2.32-2.39 (m, 1H), 1.02 (d,J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ:−77.22, −124.75. Mass spectrum (ESI, m/z): Calculated for C₂₃H₁₈ClFN₂O₄,441.1 [M+H−0.15CF₃COOH]⁺, found 441.1.

Example 46 Compound #111(Z)-5-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Step 1: 3-bromo-2-chloro-6-methoxypyridine

Into a 100-mL vial maintained with an inert atmosphere of nitrogen, to asolution of 3-bromo-2-chloro-6-methoxypyridine (2.00 g, 8.900 mmol, 1.00equiv.) in 1,4-dioxane (20 mL), added Pd(dppf)Cl₂.CH₂Cl₂ (0.36 g, 0.450mmol, 0.05 equiv.), Zn(CH₃)₂(17 mL, 17.000 mmol, 2.00 equiv.). Theresulting solution was stirred 16 h at 90° C. The mixture wasconcentrated under vacuum. The residue product was purified bychromatogram on silica gel with ethyl acetate/petroleum ether (2:98) toyield2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutanalas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₇H₈ClNO, 158.0 [M+H], found157.8.

Step 2:(Z)-5-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₃FN₄O₄, 439.2[M−0.14CF₃COOH+H], found 439.2. ¹H NMR (300 MHz, CD₃OD) δ 8.17 (s, 1H),7.52-7.56 (m, 2H), 6.94 (d, J=10.5 Hz, 1H), 6.39 (d, J=10.5 Hz, 1H),4.50-4.57 (m, 2H), 3.72 (t, J=9.3 Hz, 1H), 2.33-2.43 (m, 1H), 2.10-2.12(m, 3H), 1.51 (t, J=9.3 Hz, 3H), 1.02 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ −77.45, −119.15.

Example 47 Compound #1255-(2-(5-chloro-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Step 1:5-(2-(5-chloro-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Into a 40 ml tube were placed a solution of5-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione(200 mg, 0.456 mmol, 1 equiv.) in DMF (1 ml), and NCS (60 mg, 0.50 mmol,1.1 equv.) was then added. The mixture was stirred for 2 h at 50° C. Thereaction was monitored by LCMS. The resulting solution was extractedwith ethyl acetate (3×20 mL) of ethyl acetate. The organic layers werecombined, washed with sodium carbonate (aq.) and brine, dried andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with DCM/MeOH (30/1) to yield the product as a light yellow oil.

Mass spectrum (ESI, m/z): Calculated For C₂₃H₂₂ClFN₄O₄, 473.1[M+H]^(+, found) 473.0.

Step 2:5-(2-(5-chloro-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a lightyellow solid.

¹H NMR (400 MHz, CD₃OD, ppm) δ: 8.22 (s, 1H), 7.62 (d, J=7.2 Hz, 1H),7.01 (d, J=4.4 Hz, 1H), 6.48 (d, J=13.6 Hz, 1H), 6.38 (d, J=10.4 Hz,1H), 4.83-4.92 (m, 2H), 3.69-3.78 (m, 1H), 2.30-2.43 (m, 1H), 1.49-1.53(t, J=7 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H). ¹⁹F NMR(400 MHz, CD₃OD, ppm) δ: −121.82. Mass spectrum (ESI, m/z): CalculatedFor C₂₂H₂₀ClFN₄O₄, 459.1 [M+H]⁺, found 459.0.

Example 48 Compound #6(E)-5-(2-ethyl-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

Step 1: Ethyl2-ethyl-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)butanoate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, to a solution of ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-2,3-dihydropyridin-3-yl)acetate(400 mg, 1.4 mmol, 1 equiv.) in DMF (15 mL), followed by addition ift-BuOK (4.4 mL, 4.4 mmol, 3 equiv.) with stirring at 0° C. Iodoethane(690 mg, 4.4 mmol, 3 equiv.) was added and the resulting solution wasstirred 16 h at 20° C. The resulted solution was quenched by H₂O,extracted with EA, and the organic layer was concentrated under vacuum.The residue was purified by silica gel column with ethylacetate/petroleum ether (10:90). The collected fractions were combinedand concentrated under vacuum to yield ethyl2-ethyl-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)butanoateas a yellow solid.

Mass spectrum (ESI, m/z): Calculated For C₂₄H₂₆FNO₃, 396.2 [M+H]⁺, found396.2.

Step 2:2-ethyl-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)butan-1-oll

Into a 50-mL round-bottom, to a solution of ethyl2-cyclopentyl-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)acetate(400 mg, 1 mmol, 1 equiv.) in THF (15 mL), was added LAH (384 mg, 10mmol, 10 equiv.) with stirring at 0° C. The resulting solution wasstirred 16 h at 20° C. The resulted solution was quenched byNa₂SO₄.10H₂O. The residue was purified by silica gel column with ethylacetate/petroleum ether (10:90). The collected fractions were combinedand concentrated under vacuum to yield2-ethyl-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)butan-1-olas a yellow oil.

Mass spectrum (ESI, m/z): Calculated For C₂₂H₂₄FNO₂, 354.2 [M+H]⁺, found354.2.

Step 3:2-ethyl-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)butanal

Into a 50-mL round-bottom flask, to a solution of(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)cyclopentyl)methanol(300 mg, 0.85 mmol, 1 equiv.) in DCM (20 mL), was added DMP (1.1 g, 2.5mmol, 3 equiv.) with stirring at 0° C. The resulting solution wasstirred 3 h at 20° C. The resulted solution was quenched by Na₂S₂O₃(aq), extracted with EA, the organic layers was concentrated undervacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (10:90). The collected fractions were combinedand concentrated under vacuum to yield2-ethyl-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)butanalyellow solid.

Mass spectrum (ESI, m/z): Calculated For C₂₂H₂₂FNO₂, 352.2 (M+H), found352.2.

Step 4:(E)-5-(2-ethyl-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as ayellow solid.

¹H NMR (400 MHz, CD₃OD, ppm) δ: 8.41 (s, 1H), 8.08 (d, J=8.4 Hz, 1H),7.88 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.64-7.66 (m, 1H),7.55-7.58 (m, 1H), 7.28-7.31 (m, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.16 (s,1H), 2.32-2.34 (m, 2H), 2.04-2.13 (m, 2H), 0.83-0.87 (m, 6H). ¹⁹F NMR(400 MHz,CD₃OD, ppm) δ: −124.47. Mass spectrum (ESI, m/z): CalculatedFor C₂₄H₂₁FN₂O₄, 421.1 [M+H]⁺, found 420.9.

Example 49 Compound #95-(2-ethyl-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)butyl)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation followed by demethylation to yieldthe product as a white solid.

¹H NMR (400 MHz,CD₃OD) δ: 8.41 (s, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.88 (d,J=8.7 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.52-7.54 (m, 2H), 7.27-7.32 (m,1H), 6.78 (d, J=7.6 Hz, 1H), 4.73-4.75 (m, 1H), 2.67-2.71 (m, 1H),2.49-2.55 (m, 1H), 2.12-2.20 (m, 2H), 1.82-1.91 (m, 2H), 0.80-0.84 (m,6H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −124.51. Mass spectrum (ESI, m/z):Calculated for C₂₄H₂₃FN₂O₄, 422.3 (M+H), found 423.2.

Example 50 Compound #8(E)-5-((1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopentyl)methylene) oxazolidine-2,4-dione

Step 1: Ethyl6-bromo-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)hexanoate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, to a solution of ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-2,3-dihydropyridin-3-yl)acetate(500 mg, 1.47 mmol, 1 equiv.) in DMF (20 mL) was added t-BuOK (4.42 mL,4.42 mmol, 3 equiv.) with stirring at 0° C. 1,4-Dibromobutane (954 mg,4.42 mmol, 3 equiv.) was added and the resulting solution was stirred 16h at 20° C. The resulting solution was quenched by H₂O, extracted withEA, and the organic layers were concentrated under vacuum.

The residue was purified by silica gel column with ethylacetate/petroleum ether (10:90). The collected fractions were combinedand concentrated under vacuum to yield ethyl6-bromo-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)hexanoateas a yellow solid.

Mass spectrum (ESI, m/z): Calculated For C₂₄H₂₅BrFNO₃, 476.1 [M+H]⁺,found 476.1.

Step 2: Ethyl1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)cyclopentanecarboxylate

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, to a solution of ethyl6-bromo-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)hexanoate(500 mg, 1 mmol, 1 equiv.) in DMF (10 mL) was added t-BuOK (3.1 mL, 3mmol, 3 equiv.) with stirring at 0° C. The resulting solution wasstirred 16 h at 20° C. The resulting solution was quenched by H₂O,extracted with EA, and the organic layers was concentrated under vacuum.The residue was purified by silica gel column with ethylacetate/petroleum ether (5:95). The collected fractions were combinedand concentrated under vacuum to yield ethyl1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)cyclopentanecarboxylateas a yellow solid.

Mass spectrum (ESI, m/z): Calculated For C₂₄H₂₄FNO₃, 394.2 (M+H), found394.2.

Step 3:(E)-5-((1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopentyl)methylene) oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (400 MHz,CD₃OD, ppm) δ: 8.41 (s, 1H), 8.08 (d, J=8.8 Hz, 1H),7.87 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.71-7.74 (m, 1H),7.52-7.55 (m, 1H), 7.27-7.32 (m, 1H), 6.77 (d, J=7.2 Hz, 1H), 6.10 (s,1H), 2.38-2.42 (m, 2H), 2.14-2.18 (m, 2H), 1.78-1.91 (m, 4H). ¹⁹F NMR(400 MHz, CD₃OD, ppm) δ: −124.50. Mass spectrum (ESI, m/z): CalculatedFor C₂₄H₁₉FN₂O₄, 419.1 [M+H]⁺, found 419.2.

Example 51 Compound #75-((1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopentyl)methyl)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation followed by demethylation to yieldthe product as a white solid.

¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 11.72-11.91 (m, 2H), 8.47 (s, 1H),8.10 (d, J=8.4 Hz, 1H), 7.96-7.97 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.0 Hz,1H), 7.54-7.57 (m, 1H), 7.38-7.45 (m, 2H), 6.57 (brs, 1H), 4.56 (d, 8.4Hz, 1H), 2.67-2.71 (m, 1H), 2.01-2.14 (m, 3H), 1.84-1.99 (m, 2H),1.68-1.71 (m, 4H). ¹⁹F NMR (400 MHz, DMSO-d₆, ppm) δ: −122.21. Massspectrum (ESI, m/z): Calculated For C₂₄H₂₁FN₂O₄, 421.1 [M+H]⁺, found421.2.

Example 52 Compound #108(Z)-5-(3-methyl-2-(6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

Step 1: 6-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

Into a 20-mL microwave tube, were placed a solution of6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (400 mg, 1.869 mmol, 1.0equiv.) in THF (5 mL). Then, CH₂O (5 mL), CH₃COOH (1 mL), NaBH₃CN (450mg, 7.258 mmol, 4.0 equiv.) was added. The resulting solution wasstirred overnight at 70° C. in an oil bath. The reaction was monitoredby TLC (PE/EA=4/1). Water (5 ml) was added to the mixture and themixture was stirred for 10 minutes at room temperature. The resultingmixture was evaporated under reduced pressure. The residue was appliedonto a silica gel column with PE/EA (95/5) to6-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine obtained as ayellow oil.

Mass spectrum (EI, m/z): Calcd for C₉H₁₀BrNO, 228.0 (M+H), found, 229.7.

Step 2:4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed a solution of6-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (100 mg, 0.438mmol, 1.0 equiv.) in DMF (5 mL). Then4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (167 mg,0.658 mmol, 1.5 equiv.), Pd(dppf)Cl₂.CH₂Cl₂ (10 mg, 0.012 mmol, 0.03equiv.), KOAc (128 mg, 1.306 mmol 3.0 equiv.) were added. The resultingsolution was stirred overnight at 90° C. in an oil bath. The reactionwas monitored by TLC (PE/EA=5/1). The resulting solution was quenched bywater (10 mL). And the mixture was extracted with EtOAc (3×10 mL), thenthe organic layers combined and concentrated under vacuum. The residuewas applied onto a silica gel column with PE/EA (95/5) to yield4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazineas yellow oil.

Mass spectrum (EI, m/z): Calculated for C₁₅H₂₂BNO₃, 276.2 (M+H), found276.0.

Step 3:(Z)-5-(3-methyl-2-(6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as ayellow solid.

¹H NMR (300 MHz, Methanol-d₄) δ: 7.48-7.56 (m, 1 H), 6.90-6.95 (m, 2 H),6.78 (d, J=8.2 Hz, 1 H), 6.46-6.56 (m, 1 H), 6.36 (d, J=10.7 Hz, 1 H),4.23-4.36 (m, 2 H), 3.62-3.75 (m, 1 H), 3.29-3.31 (m, 2 H), 2.96 (s, 3H), 2.30-2.37 (m, 1 H), 1.00-1.06 (m, 3 H), 0.84-098 (m, 3 H). Massspectrum (EI, m/z): Calculated for C₂₃H₂₅N₃O₅, 410.2 (M+H), found 409.9.

Example 53 Compound #1375-(2-cyclopropyl-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-1-hydroxyethyl)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a greensolid.

¹H NMR (300 MHz, Methanol-d₄) δ 7.53 (d, J=7.3 Hz, 1 H), 6.97 (s, 1 H),6.82-6.86 (m, 1 H), 6.76-6.81 (m, 1 H), 6.46-6.58 (m, 1 H), 6.36-6.52(m, 1 H), 4.15-4.27 (m, 2 H), 3.62-3.73 (m, 1 H), 3.42-3.54 (m, 2 H),3.33-3.38 (m, 2 H), 2.25-2.40 (m, 1 H), 1.15-1.25 (m, 3 H), 1.00 (t,J=7.1 Hz, 3 H), 0.92 (t, J=7.1 Hz, 3 H). Mass spectrum (EI, m/z):Calculated for C₂₃H₂₅N₃O₅, 423.4 (M+H), found 424.2.

Example 54 Compound #276(Z)-5-(2-(6-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-oxo-2,3-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (400 MHz, CD₃OD) δ: 7.50-7.57 (m, 3H), 7.31-7.33 (m, 1H),6.57-6.60 (m, 1H), 6.33-6.46 (m, 1H), 3.65-4.27 (m, 1H), 2.31-2.43 (m,1H), 0.82-0.98 (m, 6H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −56.23, −76.94. Massspectrum (ESI, m/z): Calculated forC_(20.66)H_(16.33)F_(2.99)N₂O_(6.66), 418.3 [M−0.33CF₃COOH+H]+, found418.8.

Example 55 Compound #85(Z)-5-(2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-2,3-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (400 MHz, CD₃OD) δ: 7.48 (d, J=8.8 Hz, 1H), 7.12-7.18 (m, 2H),6.93 (d, J=8.4 Hz, 1H), 6.45-6.53 (m, 1H), 6.34 (d, J=10.8 Hz, 1H), 4.27(s, 4H), 3.64-3.69 (m, 1H), 2.30-2.35 (m, 1H), 0.98 (d, J=6.8 Hz, 3H),0.87 (d, J=6.8 Hz, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₁H₂₀N₂O₆, 397.1 (M+H), found 396.8.

Example 56 Compound #12(E)-5-(2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

Step 1: 4-bromo-3-fluoro-2-methylbenzenamine

Into a 250-mL a round bottle were placed 3-fluoro-2-methylbenzenamine(2.00 g, 15.982 mmol, 1.00 equiv.), NBS (2.99 g, 16.798 mmol, 1.051equiv.), MeCN (100 mL). The resulting solution was stirred 2 h at 25° C.The reaction was then quenched by H₂O. The resulting solution wasextracted with EA and the organic layers combined and concentrated undervacuum. The residue was purified by silica gel column with PE:EA=70:30to yield 4-bromo-3-fluoro-2-methylbenzenamine as yellow solid.

Mass spectrum (EI, m/z): Calculated for C₇H₇BrFN, 203.0 [M], found202.9.

Step 2: 5-bromo-4-fluoro-1H-indazole

Into a 100-mL round bottle were placed4-bromo-3-fluoro-2-methylbenzenamine (2.70 g, 13.233 mmol, 1.00 equiv.),AcOH (50 mL). NaNO₂ (1.10 g, 15.942 mmol, 1.21 equiv.) was then added at10° C. in portions. The resulting solution was stirred 4 h at 25° C. Thereaction was then quenched by H₂O. pH was adjusted to 8 by 50% NaOHsolution. The resulting solution was extracted with EA and the organiclayers combined and concentrated under vacuum. The residue was purifiedby silica gel column with PE:EA=70:30 to yield5-bromo-4-fluoro-1H-indazole as yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₇H₄BrFN₂, 215.0 [M+H], found214.7.

Step 3. 5-bromo-1-ethyl-4-fluoro-1H-indazole and5-bromo-2-ethyl-4-fluoro-2H-indazole

Into a 250-mL round bottle were placed 5-bromo-4-fluoro-1H-indazole(2.10 g, 9.766 mmol, 1.00 equiv), iodoethane (2.30 g, 14.747 mmol, 1.51equiv.), potassium carbonate (2.71 g, 19.608 mmol, 2.01 equiv.), DMF(100 mL). The resulting solution was stirred at 70° C. overnight. Thereaction was then quenched by H₂O. The resulting solution was extractedwith EA and the organic layers combined and concentrated under vacuum.The residue was purified by silica gel column with PE:EA=90:10 to yield5-bromo-1-ethyl-4-fluoro-1H-indazole as yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₉H₈BrFN₂, 243.0 [M+H], found244.8. and 5-bromo-2-ethyl-4-fluoro-2H-indazole as yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₉H₈BrFN₂, 243.0 (M+H), found244.7.

Step 4:(E)-5-(2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (400 MHz, CD₃OD) δ:8.18 (s, 1H), 7.60 (d, J=7.6 Hz, 1H),7.51-7.57 (m, 2H), 6.59 (d, J=7.6 Hz, 1H), 6.13 (s, 1H), 4.48-4.59 (m,2H), 2.22-2.31 (m, 2H), 2.00-2.09 (m, 2H), 1.49 (t, J=7.2 Hz, 3H), 1.32(t, J=7.2 Hz, 6H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −121.69. Mass spectrum(ESI, m/z): Calculated for C₂₃H₂₃FN₄O₄, 439.2[M+H], found 439.1.

Example 57 Compound #14(E)-5-(2-ethyl-2-(6-(1-ethyl-4-fluoro-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (300 MHz, CD₃OD) δ: 8.35 (s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.56(d, J=8.7 Hz, 1H), 7.44-7.47 (m, 1H), 6.63 (d, J=7.5 Hz, 1H), 6.15 (s,1H), 4.53-4.60 (m, 2H), 2.25-2.30 (m, 2H), 2.05-2.12 (m, 2H), 1.65 (t,J=7.2 Hz, 3H), 0.85 (t, J=7.2 Hz, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ:−120.27.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₃FN₄O₄, 439.2[M+H], found,439.1.

Example 58 Compound #11((E)-5-((1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopropyl)methylene)oxazolidine-2,4-dione

Step 1: Ethyl1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)cyclopropanecarboxylate

Into a 40-mL vial maintained with an inert atmosphere of nitrogen, wereplaced THF (5 mL). To the mixture were then added LDA (0.33 mL, 0.64mmol, 2.2 equiv.), and ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)acetate (100 mg,0.29 mmol, 1 equiv.), with stirring at 0° C. The mixture was stirred at0° C. for 20 min. Ethylene sulfate (40 mg, 0.32 mmol, 1.1 equiv.) wasadded and the resulting solution was stirred 16 h at 30° C. The mixturewas quenched by the addition of H₂O, extracted with EA, the organiclayers was concentrated under vacuum. The residue was purified by silicacal column with ethyl acetate/petroleum ether (30:70) to ethyl1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)cyclopropanecarboxylateas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₀FNO₃, 366.1 (M+H), found365.8.

Step 2:((E)-5-((1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopropyl)methylene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as ayellow solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.41 (s, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.85(d, J=8.7 Hz, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.66 (d, J=7.3 Hz, 1H),7.52-7.57 (m, 1H), 7.26-7.29 (m, 1H), 6.76 (d, J=7.3 Hz, 1H), 5.81 (s,1H), 1.43-1.45 (m, 2H), 1.29-1.31 (m, 2H). Mass spectrum (ESI, m/z):Calculated for C_(22.94)H_(15.47)F_(2.41)N₂O_(4.94), 391.1(M−0.47CF₃COOH+H), found 390.8.

Example 59 Compound #90 and #915-(2-(6-(1-ethyl-4-fluoro-1H-benzo[d]imidazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyli-dene)oxazolidine-2,4-dioneand5-(2-(6-(3-ethyl-4-fluoro-3H-benzo[d]imidazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Step 1: 4-bromo-3-fluoro-2-nitrobenzenamine

Into a 25 ml round bottom flask were placed a solution of3-fluoro-2-nitrobenzenamine (100 mg, 0.641 mmol, 1.00 equiv.) in DMF (2mL). NBS (114 mg, 0.641 mmol, 1.00 equiv.) was added. The mixture wasstirred for 1 h at 25° C. The mixture was distilled with EA. The mixturewas washed with brine.

The organic layer was concentrated under vacuum. The residue was appliedonto a silica gel column and eluted with ethyl acetate/PE (1/1) to yield4-bromo-3-fluoro-2-nitrobenzenamine as a yellow solid.

Mass spectrum (EI, m/z): Calculated for C₆H₄BrFN₂O₂, 235.9[M], found235.9.

Step 2: 4-bromo-3-fluorobenzene-1,2-diamine

Into a 50 ml flask were placed a solution of4-bromo-3-fluoro-2-nitrobenzenamine (200 mg, 0.851 mmol, 1.00 equiv.) inMeOH (30 mL), and Fe (144 mg, 2.578 mmol, 3.00 equiv.). NH₄Cl (139 mg,2.599 mmol, 3.00 equiv.) was added. The mixture was stirred overnight at70° C. The mixture was concentrated under vacuum. The residue waspurified by thin layer chromatography developed with PE/EA (1/1) toyield 4-bromo-3-fluorobenzene-1,2-diamine as yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₆H₆BrFN₂, 205.0 [M+H], found204.6.

Step 3: 5-bromo-4-fluoro-1H-benzo[d]imidazole

Into a 25 ml flask were placed a solution of4-bromo-3-fluorobenzene-1,2-diamine (70 mg, 0.341 mmol, 1.00 equiv.) informic acid (5 ml). The mixture was stirred for 2 h at 100° C. Themixture was distilled with EA. The mixture was washed with brine. Theorganic layer was concentrated under vacuum. The residue was appliedonto a silica gel column and eluted with ethyl acetate/PE (1/1) to yield5-bromo-4-fluoro-1H-benzo[d]imidazole as yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₇H₄BrFN₂, 216.0 [M+H], found216.5.

Step 4: 5-bromo-1-ethyl-4-fluoro-1H-benzo[d]imidazole compound with6-bromo-1-ethyl-7-fluoro-1H-benzo[d]imidazole

Into a 50 ml round-bottom flask were placed a solution of5-bromo-4-fluoro-1H-benzo[d]imidazole (1.30 g, 6.046 mmol, 1.00 equiv.)in DMF (10 mL). Potassium carbonate (1.19 g, 8.610 mmol, 1.40 equiv.)and iodoethane (1.60 g, 10.259 mmol, 1.70 equiv.) were added. Thereaction mixture was stirred for 15 min, and then the mixture wasstirred for 1 h at 40° C. The reaction was monitored by LCMS. Themixture was concentrated under vacuum. The residue was purified bychromatogram on silica gel with ethyl acetate/petroleum ether (1:6) toyield 5-bromo-1-ethyl-4-fluoro-1H-benzo[d]imidazole compound with6-bromo-1-ethyl-7-fluoro-1H-benzo[d]imidazole as brown solid.

Mass spectrum (ESI, m/z): Calculated for C₉H₈BrFN₂, 243.0 [M+H], found242.6.

Step 5:5-(2-(6-(1-ethyl-4-fluoro-1H-benzo[d]imidazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyli-dene)oxazolidine-2,4-dioneand5-(2-(6-(3-ethyl-4-fluoro-3H-benzo[d]imidazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compounds were prepared according to the procedure asdescribed in Example 5 going through aldol condensation by t-BuLi,dehydration followed by demethylation with TMSCl/NaI to yield theproducts as white solids.

(Z)-5-(2-(6-(1-ethyl-4-fluoro-1H-benzo[d]imidazol-5-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)ox-azolidine-2,4-dione as a white solid. ¹H NMR (300 MHz,CD₃OD) δ: 8.81 (s, 1H), 7.68-7.75 (m, 1H), 7.55-7.68 (m, 2H), 6.61 (d,J=7.2 Hz, 1H), 6.39 (d, J=10.8 Hz, 1H), 4.39-4.52 (m, 2H), 3.68-3.80 (m,1H), 2.30-2.45 (m, 1H), 1.50-1.62 (m, 3H), 1.03 (d, J=6.9 Hz, 3H), 0.95(d, J=6.6 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −132.187, −77.527. Massspectrum (ESI, m/z): Calculated for C₂₂H₂₁BrN₄O₄, 425.2 [M−0.99CF₃COOH+H], found 425.0.

(Z)-5-(2-(6-(3-ethyl-4-fluoro-3H-benzo[d]imidazol-5-yl)-2-methoxypyridin-3-yl)-3-methyl-butylidene)oxazolidine-2,4-dioneas a white solid. ¹H NMR (300 MHz, CD₃OD) δ: 8.82-8.95 (m, 1H),7.55-7.65 (m, 1H), 7.45-7.55 (m, 2H), 6.62 (d, J=7.2 Hz, 1H), 6.39 (d,J=10.8 Hz, 1H), 4.40-4.55 (m, 2H), 3.58-3.70 (m, 1H), 2.15-2.30 (m, 1H),1.45-1.55 (m, 3H), 1.03 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H). ¹⁹FNMR (300 MHz, CD₃OD) δ: −135.224, −77.475. Mass spectrum (ESI, m/z):Calculated for C₂₂H₂₁BrN₄O₄, 425.2 [M−1.34 CF₃COOH+H], found 425.0.

Example 60 Compound #2635-((6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-isopropylimidazolidine-2,4-dione

Step 1:5-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-5-isopropylimidazolidine-2,4-dione

Into a sealed tube, were placed a solution of1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-2-one(50 mg, 0.148 mmol, 1.00 equiv.) in ethanol (3 mL), then ammoniumcarbonate (50 mg, 0.318 mmol, 2.00 equiv.), ammoniumhydroxide (0.5 mL),trimethylsilanecarbonitrile (0.5 mL) were added in turn. The resultingsolution was stirred 24 h at 100° C. in an oil bath. The reaction wasmonitored by LCMS. The mixture was extracted with EtOAc, then theorganic layers combined and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:2) to yield5-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-5-isopropylimidazolidine-2,4-dioneas yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₂FN₃O₃, 408.2 (M+H), found408.1.

Step 2:5-((6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-isopropylimidazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation with TMSCl/NaI to yield the productas a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.39 (s, 1 H), 8.06 (d, J=8.7 Hz, 1 H),7.75-7.85 (m, 2 H), 7.51-7.59 (m, 2 H), 7.26-7.32 (m, 1 H), 6.73 (d,J=7.2 Hz, 1 H), 3.31-3.36 (m, 1 H), 2.85 (d, J=5.1 Hz, 1H), 2.04-2.19(m, 1 H), 1.13 (d, J=6.6 Hz, 3 H), 1.00 (d, J=6.9 Hz, 3 H). ¹⁹F NMR (300MHz, CD₃OD) δ: −76.96, −124.51. Mass spectrum (ESI, m/z): Calculated forC_(24.9)H_(21.45)F_(5.35)N₃O_(5.9), 394.1 (M−1.45CF₃COOH+H), found394.0.

Example 61 Compound #121(Z)-5-(3-methyl-2-(6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (400 MHz, CD₃OD) δ7.37 (d, J=7.4 Hz, 1H), 7.05 (d, J=8.5, Hz,1H), 6.95 (s, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.40 (d, J=7.4 Hz, 1H), 6.14(d, J=10.7 Hz, 1H), 4.12 (t, J=4.4 Hz, 2H), 3.45 (t, J=6.8 Hz, 1H),3.28-3.36 (m, 4H), 2.16-2.23 (m, 1H), 1.07 (t, J=7.0 Hz, 3H), 0.88 (d,J=6.7 Hz, 3H), 0.80 (d, J=6.6 Hz, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₃H₂₅N₃O₅, 424.2 [M+H], found 423.9.

Example 62 Compound #55(Z)-5-(2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

Step 1: Ethyl 2-(6-chloro-2-methoxypyridin-3-yl)-2-ethylbutanoate

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, to a solution of ethyl2-(6-chloro-2-methoxypyridin-3-yl)acetate (380 mg, 1.65 mmol, 1.00equiv.) in DMF (10 mL). t-BuOK (4.9 M, 4.960 mmol, 3.00 equiv.) was thenadded with stirring at 0° C. Iodoethane (774 mg, 4.960 mmol, 3.00equiv.) was added and the resulting solution was stirred 16 h at 20° C.The resulting solution was quenched by H₂O, extracted with EA, and theorganic layer was concentrated under vacuum. The residue was purified bysilica gel column with ethyl acetate/petroleum ether (10:90). Thecollected fractions were combined and concentrated under vacuum to yieldethyl 2-(6-chloro-2-methoxypyridin-3-yl)-2-ethylbutanoate as yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₄H₂₀ClNO₃, 286.1 [M+H], found285.9.

Step 2: Ethyl2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butanoate

Into a 20-mL vial maintained with an inert atmosphere of nitrogen, to asolution of ethyl 2-(6-chloro-2-methoxypyridin-3-yl)-2-ethylbutanoate(300 mg, 1.050 mmol, 1.00 equiv.) in DME (10 mL), were added1-ethyl-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(456 mg, 1.500 mmol, 1.50 equiv.), Pd(PPh₃)₄(121 mg, 0.100 mmol, 0.10equiv.), Na₂CO₃ (333 mg, 3.10 mmol, 3.00 equiv.), TBAB (338 mg, 1.050mmol, 1.00 equiv.), H₂O (2 mL). The reaction mixture was irradiated withmicrowave radiation for 15 min at 140° C. The mixture was concentratedunder vacuum. The residue purified by silica gel with ethylacetate/petroleum ether (5:95). The collected fractions were combinedand concentrated under vacuum to yield ethyl2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butanoateas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₈FN₃O₃, 414.2 [M+H], found414.3.

Step 3: Ethyl2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butan-1-ol

Into a 100-mL round bottle maintained with an inert atmosphere ofnitrogen, to a solution of ethyl2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butanoate(300 mg, 0.700 mmol, 1.00 equiv.) in DCM (15 mL). DIBAL (3 mL, 3.000mmol, 4.00 equiv.) was added with stirring at −78° C., the mixture wasstirred for 16 h at 20° C. The mixture was quenched by the addition ofNH₄Cl (aq), extracted with DCM, the organic layers was concentratedunder vacuum. The residue purified by silica gel with ethylacetate/petroleum ether (15:85). The collected fractions were combinedand concentrated under vacuum to yield ethyl2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butan-1-olas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₆FN₃O₂, 372.2 [M+H], found372.3.

Step 4:2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butanal

Into a 50-mL round-bottle were placed2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butan-1-ol(100 mg, 0.270 mmol, 1.00 equiv.), DCM (10 mL), Add DMP (228 mg, 0.540mmol, 2.00 equiv.). The mixture was stirred at 30° C. for 5 h. Themixture was quenched by the addition of Na₂S₂O₃, extracted with EA, theorganic layers was concentrated under vacuum. The residue was purifiedby TLC with ethyl acetate/petroleum ether (1:6) to2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butanalas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₄FN₃O₂, 370.2 [M+H], found370.3.

Step 5:(Z)-5-(2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

Into a 50-mL round-bottom flask, were placed(Z)-5-(2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butylidene)oxazolidine-2,4-dione(50 mg, 0.110 mmol, 1.00 equiv.), NaI (49 mg, 0.330 mmol, 3.00 equiv.),TMSCl (35 mg, 0.330 mmol, 3.00 equiv.), CH₃CN (5 mL). The resultingsolution was stirred overnight at 30° C. The reaction was then quenchedby the addition of MeOH. The resulting mixture was concentrated undervacuum. Add Na₂S₂O₃ (aq), and purified by Prep-HPLC with the followingconditions (16#-Waters 2767-5): Column, SunFire Prep C18,19*100 mm, 5um; mobile phase, Water with 0.05% TFA and CH₃CN (15% CH₃CN up to 60% in10 min, up to 100% in 0.1 min); Detector, UV 220 & 254 nm to(Z)-5-(2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dioneas white solid.

¹H NMR (300 MHz, CD₃OD) δ 8.09 (s, 1H), 7.77 (s, 1H), 7.57 (d, J=7.5 Hz,1H), 7.16 (d, J=10.8 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 6.09 (s, 1H),4.47-4.56 (m, 2H), 2.23-2.29 (m, 2H), 1.99-2.17 (m, 2H), 1.48 (t, J=7.2Hz, 3H), 0.73-0.83 (m, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ −119.21. Massspectrum (ESI, m/z): Calculated for C₂₃H₂₃FN₄O₄, 439.2 [M+H], found439.1.

Example 63 Compound #565-(2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butyl)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation followed by demethylation to yieldthe product as a white solid.

¹H NMR (300 MHz, CD₃OD) δ 8.09 (s, 1H), 7.77 (s, 1H), 7.54 (d, J=7.5 Hz,1H), 7.16 (d, J=10.8 Hz, 1H), 6.69 (d, J=7.5 Hz, 1H), 4.64-4.68 (m, 1H),4.47-4.54 (m, 2H), 2.54-2.64 (m, 1H), 2.42-2.50 (m, 1H), 2.04-2.18 (m,2H), 1.74-1.98 (m, 2H), 1.49 (t, J=7.2 Hz, 3H), 0.74-0.79 (m, 6H). ¹⁹FNMR (300 MHz, CD₃OD) δ −119.27. Mass spectrum (ESI, m/z): Calculated forC₂₃H₂₅FN₄O₄, 441.2 [M+H], found 441.4.

Example 64 Compound #35(E)-5-(2-ethyl-2-(6-(4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 62 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as ayellow solid.

¹H NMR (400 MHz, CD₃OD) δ 7.52 (d, J=7.6 Hz, 1H), 6.96 (s, 1H), 6.90 (d,J=8.2 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 6.59 (d, J=7.5 Hz, 1H), 6.18 (s,1H), 4.22-4.34 (m, 2H), 3.42-3.48 (m, 2H), 3.35-3.42 (m, 2H), 2.21-2.28(m, 2H), 1.97-2.05 (m, 2H), 1.13-1.19 (t, J=7.1 Hz, 3H), 0.75-0.84 (m,6H). Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₇N₃O₅, 438.2 [M+H],found 438.1.

Example 65 Compound #445-(2-ethyl-2-(6-(4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butyl)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation followed by demethylation to yieldthe product as a yellow solid.

¹H NMR (400 MHz, CD₃OD) δ 7.51 (d, J=7.5 Hz, 1H), 6.97 (d, J=2.1 Hz,1H), 6.84-6.90 (m, 1H), 6.78 (d, J=8.2 Hz, 1H), 6.51 (d, J=7.5 Hz, 1H),4.63-4.73 (m, 1H), 4.20-4.31 (m, 2H), 3.41-3.51 (m, 2H), 3.32-3.38 (m,2H), 2.61-2.73 (m, 1H), 2.36-2.50 (m, 1H), 1.98-2.23 (m, 2H), 1.71-1.91(m, 2H), 1.18 (t, J=7.1 Hz, 3H), 0.68-0.86 (m, 6H). Mass spectrum (ESI,m/z): Calculated for C₂₄H₂₉N₃O₅, 440.2 [M+H], found 440.4.

Example 66 Compound #285-(2-(6-(2,2-dimethyl-2H-chromen-7-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-ethylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 62 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a lightyellow solid.

¹H NMR (300 MHz, CD₃OD) δ: 7.54 (d, J=7.5 Hz, 1H), 7.10-7.23 (m, 2H),7.08 (s, 1H), 6.62 (d, J=7.5 Hz, 1H), 6.44 (d, J=9.9 Hz, 1H), 5.85 (s,1H), 5.80 (d, J=9.9 Hz, 1H), 2.05-2.30 (m, 4H), 1.46 (s, 6H), 0.75-0.90(m, 6H). Mass spectrum (ESI, m/z): Calculated for C₂₅H₂₆N₂O₅, 435.2[M+H], found 435.2.

Example 67 Compound #185-(2-(6-(2,2-dimethylchromen-7-yl)-2-methoxypyridin-3-yl)-2-ethylbutylidene)oxazolidine-2,4-dione

Step 1: 7-bromo-2,2-dimethylchroman-4-one

A solution of 1-(4-bromo-2-hydroxyphenyl)ethanone (1.00 g, 4.649 mmol,1.00 equiv.), acetone (2.70 g, 46.488 mmol, 10.00 equiv.), andpyrrolidine (330 mg, 4.640 mmol, 1.00 equiv.) in toluene (20 mL) wasstirred overnight at 80° C. The reaction was monitored by LCMS. Theresulting mixture was purified with flash column chromatography onsilica gel (ethyl acetate in petroleum ether, from 0 percent to 8percent v/v) to yield 7-bromo-2,2-dimethylchroman-4-one.

Mass spectrum (ESI, m/z): Calculated for C₁₁H₁₁BrO₂, 255.0[M+H], found256.9.

Step 2: 7-bromo-2,2-dimethyl-2H-chromene

Into a 50 ml flask were placed a solution of7-bromo-2,2-dimethylchroman-4-one (815 mg, 3.195 mmol, 1.00 equiv.) inMeOH (20 ml). NaBH₄ (488 mg, 12.899 mmol, 4.00 equiv.) was added. Themixture was stirred for 2 h. The reaction was monitored by LCMS. Themixture was concentrated under vacuum. The residue was applied on asilica gel column and eluted with PE/EA (6/1) to yield7-bromo-2,2-dimethyl-2H-chromene as white solid.

Mass spectrum (ESI, m/z): Calculated for C₁₁H₁₁O₂, 239.0 [M+H], found238.8.

Step 3:5-(2-(6-(2,2-dimethylchromen-7-yl)-2-methoxypyridin-3-yl)-2-ethylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 62 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (300 MHz, CD₃OD) δ: 7.57 (d, J=7.5 Hz, 1H), 7.21-7.23 (m, 1H),7.14-7.15 (m, 1H), 7.12 (s, 1H), 7.06 (s, 1H), 6.63 (d, J=7.2 Hz, 1H),6.17 (s, 1H), 2.84-2.89 (m, 2H), 2.18-2.32 (m, 2H), 2.05-2.10 (m, 1H),1.93-2.02 (m, 1H), 1.85-1.89 (m, 2H), 1.36 (s, 6H), 0.81-0.85 (m, 6H).Mass spectrum (ESI, m/z): Calculated for C₂₅H₂₈N₂O₅, 437.2 [M+H], found437.2.

Example 68 Compound #345-(2-ethyl-2-(6-(1-ethyl-3-methyl-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazo-lidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 62 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (400 MHz, CD₃OD) δ: 7.85 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.61(d, J=7.6 Hz, 1H), 7.40-7.48 (m, 1H), 6.75 (d, J=7.2 Hz, 1H), 6.12 (s,1H), 4.40-4.48 (m, 2H), 2.57 (s, 3H), 2.22-2.30 (m, 2H), 2.03-2.10 (m,2H), 1.41-1.50 (m, 3H), 0.78-0.83 (m, 6H). Mass spectrum (ESI, m/z):Calculated for C₂₄H₂₆N₄O₄, 435.2 [M+H], found 435.1.

Example 69 Compound #54(E)-5-(2-ethyl-2-(6-(1-ethyl-5-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 62 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (300 MHz, CD₃OD) δ: 8.05 (s, 1H), 7.85 (s, 1H), 7.57-7.60 (m,2H), 6.63-6.65 (m, 1H), 6.11 (s, 1H), 4.49-4.51 (m, 2H), 2.23-2.27 (m,2H), 2.05-2.09 (m, 2H), 1.40-1.50 (m, 3H), 0.82-0.95 (m, 6H). ¹⁹F NMR(300 MHz, CD₃OD) δ: −128.22. Mass spectrum (ESI, m/z): Calculated forC₂₃H₂₃FN₄O₄, 439.2 [M+H], found 439.3.

Example 70 Compound #435-(2-ethyl-2-(6-(1-ethyl-5-methyl-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 62 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a lightyellow solid.

¹H NMR (300 MHz, Methanol-d₄) δ: 8.01 (s, 1H), 7.70 (s, 1H), 7.62-7.64(m, 2 H), 6.43-6.45 (m, 1 H), 6.17 (s, 1 H), 4.45-4.52 (m, 2 H), 2.39(s, 3 H), 2.67-2.31 (m, 2 H), 2.03-2.10 (m, 2 H), 1.48 (t, J=7.2 Hz,3H), 0.84-0.89 (m, 6 H). Mass spectrum (ESI, m/z): Calculated forC₂₄H₂₆N₄O₄, 435.2 [M+H], found 435.2.

Example 71 Compound #1415-(2-(6-(8-ethylnaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Step 1: 1-(7-bromonaphthalen-1-yl)ethanone

A solution of 2-bromonaphthalene (2.00 g, 9.659 mmol, 1 equiv.) in DCM(40 ml) was treated with AlCl₃ (3.93 g, 29.849 mmol, 3.00 equiv.) at−10° C. and stirred until a dark green mixture was observed. The mixturewas cooled to −78° C. and acetyl chloride (1.60 g, 20.383 mmol, 2.00equiv.) was added dropwise. The reaction was stirred for 3 h at −78° C.and monitored by TLC. The reaction was warmed to 0° C. and treatedslowly with aqueous HCl (1N). After cessation of bubbling, the layerswere separated. The aqueous layer was extracted with DCM. The organiclayers were combined, washed with sodium carbonate (aq.) and brine,dried and concentrated under vacuum. The residue was applied on a silicagel column and eluted with PE/EA (6/1) to yield 2.28 g1-(7-bromonaphthalen-1-yl)ethanone as yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₂H₉BrO, 249.0[M+H], found248.8.

Step 2: 7-bromo-1-ethylnaphthalene

Into a 100 ml flask were placed a solution of1-(7-bromonaphthalen-1-yl)ethanone (2.28 g, 9.153 mmol, 1.00 equiv.) inCHCl₃(50 ml), and InBr₃ (163 mg, 0.458 mmol, 0.05 equiv.) was added inseveral portions. Et₃SiH (4.26 g, 36.636 mmol, 4.00 equiv.) was thenadded dropwise. The mixture was stirred for 6 h at room temperature. Themixture was monitored by TLC and H NMR.

The mixture was extracted with ethyl acetate (3×20 mL). The organiclayers were combined, washed with sodium carbonate (aq.) and brine,dried and concentrated under vacuum. The residue was purified by silicagel column developed with PE/EA (6/1) to yield a light yellow oil.

¹H NMR (300 MHz, CD₃OD) δ: 8.13 (s, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.70(d, J=7.8 Hz, 1H), 7.55 (d, J=6.9 Hz, 1H), 7.32-7.45 (m, 2H), 2.98-3.11(m, 2H), 1.31-1.38 (m, 3H).

Step 3:5-(2-(6-(8-ethylnaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a lightpink solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.38 (s, 1H), 8.01 (d, J=8.4 Hz, 1H),7.75-7.80 (m, 2H), 7.59-7.65 (m, 1H), 7.42-7.50 (m, 2H), 6.76 (d, J=7.2Hz, 1H), 6.41 (d, J=10.8 Hz, 1H), 3.70-3.80 (m, 1H), 3.18-3.30 (m, 2H),2.25-2.45 (m, 1H), 1.35-1.45 (m, 3H), 0.90-1.02 (m, 3H), 0.83-0.89 (m,3H). Mass spectrum (ESI, m/z): Calculated for C₂₅H₂₄N₂O₄, 417.2 [M+H],found 417.2.

Example 72 Compound #495-(2-ethyl-2-(6-(8-ethylnaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 62 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (300 MHz, CD₃OD) δ: 8.39 (s, 1H), 8.01 (d, J=8.7 Hz, 1H),7.74-7.80 (m, 2H), 7.66 (d, J=7.5 Hz, 1H), 7.43-7.52 (m, 2H), 6.80 (d,J=7.5 Hz, 1H), 6.20 (s, 1H), 3.18-3.25 (m, 2H), 2.22-2.35 (m, 2H),2.05-2.15 (m, 2H), 1.38-1.42 (m, 3H), 0.78-0.85 (m, 6H). Mass spectrum(ESI, m/z): Calculated for C₂₆H₂₆N₂O₄, 431.2 [M+H], found 431.2.

Example 73 Compound #135(Z)-5-(2-(6-(8-isopropylnaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

Step 1: 1-(7-bromonaphthalen-1-yl)ethanone

A solution of 2-bromonaphthalene (5.00 g, 24.147 mmol, 1.00 equiv.) inDCM (20 mL) was treated with AlCl₃(9.66 g, 72.440 mmol, 3.00 equiv.) at−10° C. and stirred until a dark green mixture was observed. Thereaction was cooled to −78° C. and treated slowly with acetyl chloride(3.79 g, 48.294 mmol, 2.00 equiv.). After 5 h, the reaction was warmedto 0° C. and treated slowly with aqueous HCl (1 N, 50 mL). The reactionwas monitored by LCMS. After cessation of bubbling, the layers wereseparated. The aqueous layer was then extracted with CH₂Cl₂. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated to clear oil. Chromatography (PE/EA=5:1) yielded1-(7-bromonaphthalen-1-yl)ethanone (5.20 g, 79% yield) as a yellowsolid.

Mass spectrum (ESI, m/z): Calculated for C₁₂H₉BrO, 249.0 [M+H], found250.8.

Step 2: 7-bromo-1-(prop-1-en-2-yl)naphthalene

Potassium tert-butoxide (4.69 g, 41.75 mmol, 2.00 equiv.) was added tothe suspension of methyltriphenylphosphonium bromide (14.91 g, 41.75mmol) in THF (30 mL) at ice-cooled condition. After 1 h stirring atice-cooled condition, a solution of 1-(7-bromonaphthalen-1-yl)ethanone(5.20 g, 20.875 mmol) in THF (10 mL) was added dropwise. Then thereaction mixture was stirred at room temperature for 1 h. The reactionwas monitored by NMR. The reaction mixture was diluted with pet etherand filtered, filtrate was concentrated to yield7-bromo-1-(prop-1-en-2-yl)naphthalene as a pale yellow oil followingcolumn chromatographic purification of the residue using PE:EA=15:1.

¹H NMR (300 MHz, CD₃OD) δ: 8.21 (s, 1H), 7.71 (d, J=6.3 Hz, 2H), 7.56(d, J=6.6 Hz, 1H), 7.42-7.47 (m, 1H), 7.31 (d, J=6.0 Hz, 1H), 5.43 (s,1H), 5.04 (s, 1H), 2.20 (s, 3H).

Step 3: Ethyl2-(2-methoxy-6-(8-(prop-1-en-2-yl)naphthalen-2-yl)pyridin-3-yl)-3-methylbutanoate

The title compound was prepared according to the procedure as describedin Example 4 going through metalation with t-BuLi followed by treatmentwith diethyl oxalate, acid-catalyzed dihydroxylation with TFA andtriethyl silane, followed by alkylation with i-Pr—I and LDA to yield theproduct as a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₆H₂₉NO₃, 404.2 [M+H], found404.3.

Step 4: ethyl2-(6-(8-isopropylnaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanoate

Into a 25-mL round-bottom flask, were placed ethyl2-(2-methoxy-6-(8-(prop-1-en-2-yl)naphthalen-2-yl)pyridin-3-yl)-3-methylbutanoate(500 mg, 1.239 mmol, 1.00 equiv.), Pd/C in MeOH (8 mL). To the mixturewas then introduced H₂. The resulting solution was stirred overnight at25° C. The reaction was monitored by LCMS. The solids were filtered out.The resulting solution was concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:15) to yield ethyl2-(6-(8-isopropylnaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanoateas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₆H₃₁NO₃, 406.2 [M+H], found406.1.

Step 5:(Z)-5-(2-(6-(8-isopropylnaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (400 MHz, CD₃OD) δ: 8.43 (s, 1H), 7.98 (d, J=8.4 Hz, 1H),7.73-7.76 (m, 2H), 7.72 (d, J=7.2 Hz, 1H), 7.60 (d, J=7.2 Hz, 2H), 6.73(d, J=7.2 Hz, 1H), 6.35 (d, J=10.4 Hz, 1H), 3.87-3.94 (m, 1H), 3.70-3.75(m, 1H), 2.34-2.41 (m, 1H), 1.42 (d, J=6.8 Hz, 6H), 1.00 (d, J=6.8 Hz,3H), 0.93 (d, J=6.8 Hz, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₆H₂₆N₂O₄, 431.2 [M+H], found 431.2.

Example 74 Compound #19(E)-5-(2-ethyl-2-(6-(8-isopropylnaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 62 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (300 MHz, CD₃OD) δ: 8.45 (s, 1H), 7.99 (d, J=8.7 Hz, 1H),7.74-7.77 (m, 2H), 7.65 (d, J=7.5 Hz, 1H), 7.53 (d, J=5.1 Hz, 2H), 6.79(d, J=7.2 Hz, 1H), 6.19 (s, 1H), 3.90-3.95 (m, 1H), 2.25-2.32 (m, 2H),2.02-2.10 (m, 2H), 1.43 (d, J=6.6 Hz, 6H), 0.85 (t, J=7.5 Hz, 6H). Massspectrum (ESI, m/z): Calculated for C₂₇H₂₈N₂O₄, 445.2 [M+H], found445.2.

Example 75 Compound #1435-(3-methyl-2-(2-oxo-6-(8-(trifluoromethyl)naphthalen-2-yl)-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

Step 1: 8-iodonaphthalen-2-ol

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed a 8-aminonaphthalen-2-ol (5.00 g,31.410 mmol, 1.00 equiv) in H₂O (50 ml). HCl (15 mL, 3 N) and NaNO₂(3.90 g in 10 mL H₂O) were added at 0° C. The resulting solution wasstirred 30 min at 0° C. KI (4.40 g in 10 mL H₂O) was then added. Theresulting solution was stirred 2 h at 0° C. The reaction was monitoredby LCMS. The resulting solution was extracted with EtOAc, and then theorganic layers combined and concentrated under vacuum. The residue wasapplied onto a silica gel column with EA/PE (1:10) to yield8-iodonaphthalen-2-ol as light red solid.

Mass spectrum (ESI, m/z): Calculated for C₁₀H₇IO, 271.0 [M+H], found270.9.

Step 2: 8-iodonaphthalen-2-yl trifluoromethanesulfonate

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed a 8-iodonaphthalen-2-ol (1600 mg,5.924 mmol, 1.00 equiv.) in ethylether (30 ml). NaH (710 mg, 29.622mmol, 5.00 equiv.) was added at 0° C. The resulting solution was stirred1 h at 25° C. Tf₂O (2512 mg, 8.903 mmol, 1.50 equiv.) was then added.The reaction was monitored by TLC. The resulting solution was extractedwith EtOAc, and then the organic layers combined and concentrated undervacuum. The residue was applied onto a silica gel column with EA/PE(1:10) to yield 8-iodonaphthalen-2-yl trifluoromethanesulfonate asyellow oil.

¹H NMR (300 MHz, CDCl₃) δ: 8.18-8.16 (m, 1 H), 8.08 (s, 1 H), 7.91-7.88(m, 2 H), 7.44-7.41 (m, 1 H), 7.31-7.26 (m, 1 H).

Step 3: 8-(trifluoromethyl)naphthalen-2-yl trifluoromethanesulfonate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed a 8-iodonaphthalen-2-yltrifluoromethanesulfonate (2300 mg, 5.720 mmol, 1.00 equiv.) in DMF (50mL). CuI (5.45 g, 28.598 mmol, 4.00 equiv.), methyl2,2-difluoro-2-(fluorosulfonyl)acetate (1651 mg, 8.595 mmol, 4.00equiv.) were then added.

The resulting solution was stirred 2 h at 100° C. The reaction wasmonitored by LCMS. The resulting solution was extracted with EtOAc, andthen the organic layers combined and concentrated under vacuum. Theresidue was applied onto a silica gel column with EA/PE (1:15) to yield8-(trifluoromethyl)naphthalen-2-yl trifluoromethanesulfonate as yellowoil.

¹H NMR (400 MHz, CDCl₃) δ: 8.13-7.97 (m, 4 H), 7.74-7.72 (m, 1 H),7.55-7.50 (m, 1 H).

Step 4:5-(3-methyl-2-(2-oxo-6-(8-(trifluoromethyl)naphthalen-2-yl)-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as anoff-white solid.

¹H NMR (400 MHz, Methanol-d₄), δ: 8.35 (s, 1 H), 8.21 (d, J=8.0 Hz, 1H), 8.16 (d, J=8.8 Hz, 1 H), 8.01 (d, J=7.2 Hz, 1 H), 7.87-7.89 (m, 1H), 7.66-7.70 (m, 1 H), 7.59-7.63 (m, 1 H), 6.66-6.71 (m, 1 H), 6.38 (d,J=10.8 Hz, 1 H), 3.73 (t, J=10.4 Hz, 1 H), 2.35-2.41 (m, 1 H), 1.00-1.02(m, 3 H), 0.90-0.94 (m, 3 H). ¹⁹F NMR (400 MHz, Methanol-d₄) δ: −60.852.Mass spectrum (ESI, m/z): Calculated for C₂₄H₁₉F₃N₂O₄, 457.1 [M+H],found 457.1.

Example 76 Compound #235-(2-ethyl-2-(2-oxo-6-(8-(trifluoromethyl)naphthalen-2-yl)-1,2-dihydropyridin-3-yl)butylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 62 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as alight-pink solid.

¹H NMR (300 MHz, Methanol-d₄), δ: 8.34 (s, 1 H), 8.20-8.12 (m, 2 H),7.99-7.97 (m, 1 H), 7.89-7.83 (m, 1 H), 7.67-7.61 (m, 2 H), 6.72-6.68(m, 1 H), 6.14 (s, 1 H), 2.29-1.98 (m, 4 H), 0.84-0.77 (m, 6 H). ¹⁹F NMR(300 MHz, Methanol-d₄) δ: −60.70, 77.66. Mass spectrum (ESI, m/z):Calculated for C₂₅H₂₁F₃N₂O₄.471.1 [M+H], found 471.1.

Example 77 Compound #142 and #310(Z)-7-(5-(1-(2,4-dioxooxazolidin-5-ylidene)-3-methylbutan-2-yl)-6-oxo-1,6-dihydropyridin-2-yl)-1-naphthonitrileand(E)-7-(5-(1-(2,4-dioxooxazolidin-5-ylidene)-3-methylbutan-2-yl)-6-oxo-1,6-dihydropyridin-2-yl)-1-naphthonitrile

Step 1: 8-cyanonaphthalen-2-yl trifluoromethanesulfonate

Into a 50 mL round-bottom flask were placed a solution of8-iodonaphthalen-2-yl trifluoromethanesulfonate (2.70 g, 6.714 mmol,1.00 equiv.) in DMF (20 mL). Zn(CN)₂ (394 mg, 3.357 mmol, 0.50 equiv.),Pd(PPh₃)₄(155 mg, 0.134 mmol, 0.02 equiv.) were then added. The mixturewas stirred for 2 h at 120° C. under nitrogen. The reaction wasmonitored by TLC. The mixture was extracted with ethyl acetate (3×40mL). The organic layers were combined, washed with sodium carbonate(aq.) and brine, dried and concentrated under vacuum. The residue waspurified by chromatogram on silica gel with ethyl acetate/petroleumether (1:1) to yield 8-cyanonaphthalen-2-yl trifluoromethanesulfonate asyellow oil.

¹H NMR (400 MHz, CDCl₃) δ: 8.13-8.23 (m, 2H), 8.03-8.12 (m, 2H),7.63-7.73 (m, 1H), 7.55-7.63 (m, 1H).

Step 2:(Z)-7-(5-(1-(2,4-dioxooxazolidin-5-ylidene)-3-methylbutan-2-yl)-6-oxo-1,6-dihydropyridin-2-yl)-1-naphthonitrileand(E)-7-(5-(1-(2,4-dioxooxazolidin-5-ylidene)-3-methylbutan-2-yl)-6-oxo-1,6-dihydropyridin-2-yl)-1-naphthonitrile

The title compounds were prepared according to the procedure asdescribed in Example 5 going through aldol condensation by t-BuLi,dehydration followed by demethylation with TMSCl/NaI to yield

(Z)-7-(5-(1-(2,4-dioxooxazolidin-5-ylidene)-3-methylbutan-2-yl)-6-oxo-1,6-dihydropyridin-2-yl)-1-naphthonitrileas a light yellow solid. ¹H NMR (400 MHz, CD₃OD) δ: 8.44 (s, 1H), 8.27(d, J=8.4 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.05-8.10 (m, 1 H), 7.92-7.95(m, 1H), 7.65-7.73 (m, 1H), 7.63 (d, J=7.6 Hz, 1H), 6.80 (d, J=7.2 Hz,1H), 6.35 (d, J=10.4 Hz, 1H), 3.70-3.80 (m, 1H), 2.25-2.40 (m, 1H), 1.01(d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₄H₁₉N₃O₄: 414.1 [M+H], found: 414.2.

and(E)-7-(5-(1-(2,4-dioxooxazolidin-5-ylidene)-3-methylbutan-2-yl)-6-oxo-1,6-dihydropyridin-2-yl)-1-naphthonitrileas a light yellow solid. ¹H NMR (400 MHz, CD₃OD) δ: 8.42 (s, 1H), 8.27(d, J=8.4 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 8.09 (d, J=7.2 Hz, 1H),7.90-8.0 (m, 1H), 7.65-7.70 (m, 1H), 7.58-7.63 (m, 1H), 6.72-6.80 (m,1H), 6.18-6.43 (m, 1H), 3.74-4.37 (m, 1H), 2.30-2.50 (m, 1H), 0.95-1.0(m, 3H), 0.82-0.90 (m, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₄H₁₉N₃O₄: 414.1 [M+H], found: 414.2.

Example 78 Compound #32(E)-5-(2-(6-(6,8-difluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-ethylbutylidene)oxazolidine-2,4-dione

Step 1: 6,8-difluoronaphthalen-2-ol

Into a 100-mL round-bottom flask, were placed a solution of6,8-difluoro-3,4-dihydronaphthalen-2(1H)-one (2.00 g, 10.979 mmol, 1.00equiv.) in acetonitrile (20 mL). NBS (2.15 g, 12.077 mmol, 1.10 equiv.)and TMsOTf (122.008 mg, 0.549 mmol, 0.05 equiv.) were then added to thesolution in turn. The resulting solution was stirred for 5.0 h at 30° C.The reaction was monitored by NMR. The resulting solution was extractedwith EtOAc, and then the organic layers combined and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:3) to yield 6,8-difluoronaphthalen-2-ol as awhite solid.

¹H NMR (400 MHz, CD₃OD) δ: 7.95 (s, 1H), 7.89 (d, J=9.0 Hz, 1H), 7.45(d, J=6.9 Hz, 1H), 7.26 (d, J=6.0 Hz, 1H), 7.07-7.13 (m, 1H), 5.10 (brs,1H).

Step 2: 6,8-difluoronaphthalen-2-yl trifluoromethanesulfonate

Into a 25-mL round-bottom flask, were placed a solution of6,8-difluoronaphthalen-2-ol (50 mg, 0.278 mmol, 1.00 equiv.) in Et₂O (6mL). NaH (16.651 mg, 0.694 mmol, 2.50 equiv.) was then added to thesolution. The resulting solution was stirred for 1.0 h at 0° C. ThenTf₂O (117.459 mg, 0.416 mmol, 1.50 equiv.) was added. The reaction wasmonitored by NMR. The resulting solution was extracted with EtOAc, thenthe organic layers combined and concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1:5) to yield 6,8-difluoronaphthalen-2-yl trifluoromethanesulfonate asa white solid.

¹H NMR (300 MHz, CD₃OD) δ: 7.95 (s, 1H), 7.89 (d, J=9.0 Hz, 1H), 7.45(d, J=6.9 Hz, 1H), 7.26 (d, J=6.0 Hz, 1H), 7.07-7.13 (m, 1H).

Step 3:(E)-5-(2-(6-(6,8-difluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-ethylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 62 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (300 MHz, CD₃OD) δ: 8.38 (s, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.90(d, J=8.7 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H),7.23-7.30 (m, 1H), 6.80 (d, J=7.5 Hz, 1H), 6.16 (s, 1H), 2.23-2.30 (m,2H), 2.01-2.06 (m, 2H), 0.83 (t, J=7.2 Hz, 6H). ¹⁹F NMR (300 MHz, CD₃OD)δ: −119.91, −119.37. Mass spectrum (ESI, m/z): Calculated forC₂₄H₂₀F₂N₂O₄, 439.1 [M+H], found 439.1.

Example 79 Compound #10(E)-5-(2-(6-(5,7-difluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-ethylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 62 going through aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (400 MHz, CD₃OD) δ: 8.15 (s, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.74(d, J=7.6 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.45 (d, J=9.2 Hz, 1H),7.11-7.16 (m, 1H), 6.71 (d, J=7.6 Hz, 1H), 6.00 (s, 1H), 2.12-2.21 (m,2H), 1.83-2.01 (m, 2H), 0.90 (t, J=6.4 Hz, 6H). ¹⁹F NMR (400 MHz, CD₃OD)δ: −111.77, −120.35. Mass spectrum (ESI, m/z): Calculated forC₂₄H₂₀F₂N₂O₄, 439.1 [M+H], found 438.9.

Example 80 Compound #13(E)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-((2-oxopyrrolidin-3-ylidene)methyl)pentan-3-yl)pyridin-2(1H)-one

Step 1: tert-butyl 2-oxopyrrolidine-1-carboxylate

Into a 250-mL round-bottom flask, were placed pyrrolidin-2-one (1.00 g,11.750 mmol, 1.00 equiv.), DCM (20 mL), Boc₂O (3.85 g, 17.625 mmol, 1.50equiv.), TEA (3.57 g, 35.251 mmol, 3.00 equiv.), DMAP (143 mg, 1.175mmol, 0.10 equiv.). The resulting solution was stirred overnight at 25°C. The reaction was monitored by TLC (PE:EA=3:1). The resulting solutionwas concentrated. The residue was applied onto a silica gel column withPE:EA=3:1 to yield tert-butyl 2-oxopyrrolidine-1-carboxylate lightyellow oil.

¹H NMR (300 MHz, CDCl₃) δ: 3.75-3.80 (m, 2H), 2.51-2.56 (m, 2H),1.97-2.07 (m, 2H), 1.55 (s, 9H).

Step 2:(E)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-((2-oxopyrrolidin-3-ylidene)methyl)pentan-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 62 going through aldol condensation by t-BuLi, dehydrationfollowed by deprotection of Boc group and demethylation with TMSCl/NaIto yield the product as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.15 (s, 1H), 7.83 (s, 1H), 7.62 (d, J=7.2Hz, 1H), 7.23 (d, J=11.1 Hz, 1H), 6.79 (d, J=7.5 Hz, 1H), 6.62-6.64 (m,1H), 4.53-4.58 (m, 2H), 3.29-3.33 (m, 2H), 2.54-2.58 (m, 2H), 2.28-2.35(m, 2H), 1.93-2.00 (m, 2H), 1.52-1.57 (m, 3H), 0.81-0.86 (m, 6H). ¹⁹FNMR (300 MHz, CD₃OD) δ: −119.22. Mass spectrum (ESI, m/z): Calculatedfor C₂₄H₂₇FN₄O₂, 423.2 [M+H], found 423.1.

Example 81 Compound #406-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-((2-oxopyrrolidin-3-yl)methyl)pentan-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation followed by demethylation to yieldthe product as a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.10 (s, 1H), 7.80 (s, 1H), 7.67 (d, J=7.2Hz, 1H), 7.19 (d, J=11.2 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 4.50-4.58 (m,2H), 3.43-3.50 (m, 1H), 3.10-3.20 (m, 2H), 2.85-2.99 (m, 2H), 2.12-2.28(m, 2H), 1.82-1.95 (m, 1H), 1.55-1.73 (m, 1H), 1.48-1.55 (m, 4H),1.28-1.40 (m, 1H), 1.05-1.19 (m, 1H), 0.75-0.95 (m, 6H). ¹⁹F NMR (400MHz, CD₃OD) δ: −119.17 Mass spectrum (ESI, m/z): Calculated forC₂₄H₂₉FN₄O₂, 425.2 [M+H], found 425.2.

Example 82 Compound #25(E)-6-(4-ethyl-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(3-((2-oxopyrrolidin-3-ylidene)methyl)pentan-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 62 going through aldol condensation by t-BuLi, dehydrationfollowed by deprotection of Boc group and demethylation with TMSCl/NaIto yield the product as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ: 7.86 (s, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.42(d, J=7.5 Hz, 1H), 7.18 (s, 1H), 7.07-7.11 (m, 1H), 4.90 (s, 1H),4.25-4.28(m, 2H), 3.37-3.45 (m, 2H), 3.32-3.35 (m, 2H), 3.15-3.18 (m,2H), 2.71-2.79 (m, 1H), 1.90-2.00 (m, 1H), 1.60-1.80 (m, 4H), 1.08-1.15(m, 3H), 0.88-0.90 (m, 3H), 0.81-0.85 (m, 3H). ¹⁹F NMR (300 MHz,DMSO-d₆) δ: −137.12. Mass spectrum (ESI, m/z): Calculated forC₂₅H₃₀FN₃O₃, 440.2 [M+H], found 440.1.

Example 83 Compound #149 and #150(E)-6-(8-fluoronaphthalen-2-yl)-3-(3-methyl-1-(2-oxopyrrolidin-3-ylidene)butan-2-yl)pyridin-2(1H)-oneand(Z)-6-(8-fluoronaphthalen-2-yl)-3-(3-methyl-1-(2-oxopyrrolidin-3-ylidene)butan-2-yl)pyridin-2(1H)-one

The title compounds were prepared according to the procedure asdescribed in Example 5 going through aldol condensation by t-BuLi,dehydration followed by deprotection of Boc group and demethylation withTMSCl/NaI to yield(E)-6-(8-fluoronaphthalen-2-yl)-3-(3-methyl-1-(2-oxopyrrolidin-3-ylidene)butan-2-yl)pyridin-2(1H)-oneas a white solid

¹H NMR (300 MHz, CD₃OD) δ: 8.35 (s, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.80(d, J=8.7 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.46-7.53 (m, 2H), 7.22-7.28(m, 1H), 6.67 (d, J=7.2 Hz, 1H), 6.47 (d, J=10.5 Hz, 1H), 4.57-4.63 (m,1H), 3.32-3.37 (m, 2H), 2.72-2.87 (m, 2H), 2.37-2.47 (m, 1H), 0.92 (d,J=6.6 Hz, 3H), 0.81 (d, J=6.6 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ:−124.53. Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₃FN₂O₂, 391.0[M+H], found. 391.0;

and(Z)-6-(8-fluoronaphthalen-2-yl)-3-(3-methyl-1-(2-oxopyrrolidin-3-ylidene)butan-2-yl)pyridin-2(1H)-oneas a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.41 (s, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.81(d, J=8.7 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.47-7.56 (m, 2H), 7.22-7.28(m, 1H), 6.75 (d, J=7.2 Hz, 1H), 6.55 (d, J=10.5 Hz, 1H), 3.51-3.60 (m,1H), 3.35-3.45 (m, 2H), 2.85-2.95 (m, 2H), 2.13-2.24 (m, 1H), 0.98 (d,J=6.6 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ:−124.49. Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₃FN₂O₂, 391.0[M+H], found, 391.0.

Example 84 Compound #144 and #145Syn-6-(8-fluoronaphthalen-2-yl)-3-(3-methyl-1-(2-oxopyrrolidin-3-yl)butan-2-yl)pyridin-2(1H)-oneandanti-6-(8-fluoronaphthalen-2-yl)-3-(3-methyl-1-(2-oxopyrrolidin-3-yl)butan-2-yl)pyridin-2(1H)-one

The title compounds were prepared according to the procedure asdescribed in Example 8 step 1 by hydrogenation followed by demethylationto yield the products.

Syn-6-(8-fluoronaphthalen-2-yl)-3-(3-methyl-1-(2-oxopyrrolidin-3-yl)butan-2-yl)pyridin-2(1H)-oneas a white solid. ¹H NMR (300 MHz, CD₃OD) δ: 8.38 (s, 1H), 8.03 (d,J=8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.47-7.56(m, 2H), 7.22-7.29 (m, 1H), 6.79 (d, J=7.5 Hz, 1H), 3.31-3.32 (m, 1H),3.16-3.22 (m, 1H), 2.90-3.00 (m, 1H), 2.06-2.29 (m, 3H), 1.86-1.93 (m,1H), 1.71-1.78 (m, 1H), 1.56-1.65 (m, 1H), 0.96 (d, J=6.9 Hz, 3H), 0.89(d, J=6.9 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −124.52.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₅FN₂O₂, 393.2 [M+H],found, 393.0.

andanti-6-(8-fluoronaphthalen-2-yl)-3-(3-methyl-1-(2-oxopyrrolidin-3-yl)butan-2-yl)pyridin-2(1H)-oneas a white solid. ¹H NMR (300 MHz, CD₃OD) δ: 8.38 (s, 1H), 8.03 (d,J=8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.47-7.54(m, 2H), 7.22-7.28 (m, 1H), 6.75 (d, J=7.5 Hz, 1H), 3.11-3.21 (m, 2H),2.85-2.95 (m, 1H), 2.27-2.37 (m, 2H), 1.98-2.08 (m, 2H), 1.61-1.76 (m,2H), 0.99 (d, J=6.9 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H). ¹⁹F NMR (300 MHz,CD₃OD) δ: −124.55. Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₅FN₂O₂,393.2 [M+H], found. 393.0.

Example 85 Compound #46 and #476-(1-ethyl-4-fluoro-1H-indazol-6-yl)-5-fluoro-3-(3-((2-oxo-2,5-dihydro-1H-pyrrol-3-yl)methyl)pentan-3-yl)pyridin-2(1H)-oneand(E)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-5-fluoro-3-(3-((2-oxopyrrolidin-3-ylidene)methyl)pentan-3-yl)pyridin-2(1H)-one

Step 1: Ethyl 2-(6-chloro-5-fluoro-2-methoxypyridin-3-yl)acetate

Into a 100-mL round-bottom flask, were placed2-(6-chloro-5-fluoro-2-methoxypyridin-3-yl)acetonitrile (800 mg, 3.9mmol, 1.00 equiv.). EtOH (10 mL), SOCl₂ (2 mL) were added. The reactionwas stirred overnight at 90° C. for 16 h. The reaction progress wasmonitored by TLC. The reaction was concentrated under vacuum. Theresidue product was purified by chromatogram on silica gel with ethylacetate/petroleum ether (10:90) to yield ethyl2-(6-chloro-5-fluoro-2-methoxypyridin-3-yl)acetate as yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₁₀H₁₁ClFNO₃, 248.0 [M+H],found 247.8.

Step 2:6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-5-fluoro-3-(3-((2-oxo-2,5-dihydro-1H-pyrrol-3-yl)methyl)pentan-3-yl)pyridin-2(1H)-oneand(E)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-5-fluoro-3-(3-((2-oxopyrrolidin-3-ylidene)methyl)pentan-3-yl)pyridin-2(1H)-one

Into a 50 mL round bottle, to a solution of (E)-tert-butyl3-(2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-5-fluoro-2-methoxypyridin-3-yl)butylidene)-2-oxopyrrolidine-1-carboxylate(30 mg, 0.054 mmol, 1.00 equiv.) in CH₃CN (5 mL) were added NaI (24 mg,0.162 mmol, 3.00 equiv.), TMSCl (18 mg, 0.162 mmol, 3.00 equiv.). Theresulting mixture was stirred at 30° C. overnight. The solvent wasevaporated and the residue was purified by Prep-HPLC with the followingconditions (16#-Waters 2767-5): Column, SunFire Prep C18,19*100 mm, 5um; mobile phase, Water with 0.05% TFA and CH₃CN (50% CH₃CN up to 65% in15 min, up to 100% in 0.1 min); Detector, UV 220 & 254 nm. The resultingsolution was concentrated under vacuum to yield

6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-5-fluoro-3-(3-((2-oxo-2,5-dihydro-1H-pyrrol-3-yl)methyl)pentan-3-yl)pyridin-2(1H)-oneas white solid. ¹H NMR (300 MHz, CD₃OD) δ 8.08 (s, 1H), 7.89 (s, 1H),7.28-7.36 (m, 2H), 4.51-4.85 (m, 2H), 3.87-3.88 (m, 1H), 2.91-3.04 (m,2H), 2.22-2.32 (m, 1H), 1.72-1.94 (m, 4H), 1.51-1.57 (m, 1H), 1.45-1.49(m, 3H), 1.07-1.12 (m, 3H), 0.93-0.98 (m, 3H). ¹⁹F NMR (300 MHz, CD₃OD)δ −77.06, −120.55, −135.05. Mass spectrum (ESI, m/z): Calculated forC_(26.68)H_(30.34)F_(2.02)N₇O_(1.68): 441.2[M−1.11CF₃COOH+H], found:441.2.

and(E)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-5-fluoro-3-(3-((2-oxopyrrolidin-3-ylidene)methyl)pentan-3-yl)pyridin-2(1H)-oneas a white solid.

¹H NMR (300 MHz, CD₃OD) δ 8.09 (d, J=1.0 Hz, 1H), 7.81 (s, 1H), 7.54 (d,J=10.9 Hz, 1H), 7.25 (d, J=11.2 Hz, 1H), 5.51 (d, J=6.8 Hz, 1H),4.40-4.59 (m, 2H), 3.99 (d, J=7.2 Hz, 1H), 3.12-3.23 (m, 2H), 2.99-3.12(m, 1H), 2.10-2.36 (m, 2H), 1.86-1.96 (m, 2H), 1.64-1.74 (m, 3H),11.4-1.56 (m, 3H), 0.89-1.01 (m, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ −77.39,−120.30. Mass spectrum (ESI, m/z): Calculated forC_(38.64)H_(33.32)F_(23.96)N₄O_(16.64): 441.2 [M−7.32CF₃COOH+H], found:441.2.

Example 86 Compound #1466-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-methyl-1-(3-methyl-2-oxopyrrolidin-3-yl)butan-2-yl)pyridin-2(1H)-one

Step 1:(E)-tert-butyl3-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutylidene)-2-oxopyrrolidine-1-carboxylate

The title compound was prepared according to the procedure as describedin Example 5 going through aldol condensation by t-BuLi, dehydration toyield the product as a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₉H₃₅FN₄O₄, 523.3. [M+H],found. 523.3.

Step 2:Tert-butyl3-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)-2-oxopyrrolidine-1-carboxylate

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation to yield the product as a lightyellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₉H₃₇FN₄O₄, 525.3 [M+H], found525.5.

Step 3:Tert-butyl3-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)-3-methyl-2-oxopyrrolidine-1-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed tert-butyl3-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)-2-oxopyrrolidine-1-carboxylate(80 mg, 0.152 mmol, 1.00 equiv), THF (5 ml). This was followed by theaddition LiHMDS (0.5 ml, 0.457 mmol, 3.00 equiv) dropwise with stirringat −78° C. The reaction was stirred 1 h at −78° C. CH₃I (65 mg, 0.457mmol, 3.00 equiv) was added to the resulting solution with stirring at−78° C. The reaction was stirred 1 h at −78° C. and maintaining thetemperature at 25° C. for 1 h. The reaction progress was monitored byTLC (PE:EA=3:1). The reaction was then quenched by H₂O. The resultingmixture was extracted with DCM (3×10 mL).

The organic layers were combined, dried over Na₂SO₄, filtered andconcentrated. The residue obtained was purified by silica gelchromatography (0-30% EtOAc/petroleum ether) to yield a light yellowoil.

Mass spectrum (ESI, m/z): Calculated for C₃₀H₃₉FN₄O₄, 539.3 [M+H], found539.2.

Step 4:6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-methyl-1-(3-methyl-2-oxopyrrolidin-3-yl)butan-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation with TMSCl/NaI to yield the productas an off-white solid.

¹H NMR (300 MHz, DMSO-d₆) δ: 8.05-8.20 (m, 2H), 7.36-7.49 (m, 3H), 6.83(m, 1H), 4.48-4.55 (m, 2H), 2.73-3.11 (m, 3H), 1.61-1.91 (m, 4H),1.39-1.46 (m, 4H), 0.89-0.99 (m, 3H), 0.76-0.83 (m, 6H). ¹⁹F NMR (300MHz, DMSO-d₆) δ: −74.73, −117.89. Mass spectrum (ESI, m/z): Calculatedfor C₂₄H₂₉FN₄O₂, 425.2 [M+H−1.89CF₃COOH], found 425.1.

Example 87 Compound #147 and #148Syn-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-methyl-1-(2-oxopyrrolidin-3-yl)butan-2-yl)pyridin-2(1H)-oneand6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-methyl-1-(2-oxopyrrolidin-3-yl)butan-2-yl)pyridin-2(1H)-one

The title compounds were prepared according to the procedure asdescribed in Example 8 step 1 by hydrogenation to yield

syn-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-methyl-1-(2-oxopyrrolidin-3-yl)butan-2-yl)pyridin-2(1H)-oneas a light yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ: 7.37 (s, 1H),7.26-7.34 (m, 1H), 6.75-6.97 (m, 3H), 6.55-6.65 (m, 1H), 3.30-3.36 (m,2H), 3.00-3.15 (m, 2H), 2.60-2.73 (m, 1H), 2.04-2.08 (m, 2H), 1.71-1.88(m, 2H), 1.39-1.61 (m, 2H), 1.16-1.24 (m, 3H), 0.88 (d, J=6.6 Hz, 3H),0.77 (d, J=7.5 Hz, 3H). ¹⁹F NMR (300 MHz, DMSO-d₆) δ: −74.57, −108.18.Mass spectrum (ESI, m/z): Calculated forC_(32.9)H_(31.95)F_(15.85)N₄O_(11.9), 411.0 [M−4.95CF₃COOH+H], found,411.0.

andanti-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-methyl-1-(2-oxopyrrolidin-3-yl)butan-2-yl)pyridin-2(1H)-oneas a light yellow solid. ¹H NMR (300 MHz, CD₃OD) δ: 7.47 (d, J=7.2 Hz,1H), 6.80 (s, 1H), 6.65-6.72 (m, 2H), 3.32-3.39 (m, 2H), 3.14-3.19 (m,2H), 2.92-2.94 (m, 1H), 2.21-2.33 (m, 2H), 1.95-2.00 (m, 2H), 1.58-1.71(m, 2H), 1.24-1.29 (m, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.83 (d, J=7.5 Hz,3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −77.47, −108.87. Mass spectrum (ESI,m/z): Calculated for C_(28.28)H_(29.64)F_(8.92)N₄O_(7.28), 411.0(M−2.64CF₃COOH+H), found, 411.0.

Example 88 Compound #586-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-((2-oxopiperidin-3-yl)methyl)pentan-3-yl)pyridin-2(1H)-one

Step 1: ethyl 4-(6-chloro-2-methoxypyridin-3-yl)-4-ethylhex-2-enoate

To a solution of ethyl 2-(trimethylsilyl)acetate (425 mg, 2.652 mmol) inTHF (10 mL) was added LiHMDS (2.66 mL) at −78° C. for 1 h. Then2-(6-chloro-2-methoxypyridin-3-yl)-2-ethylbutanal (300 mg, 1.241 mmol)in THF (5 mL) was added. The resulting mixture was stirred at 25° C.overnight. After cooling down to room temperature, the reaction wasquenched with H₂O (10 mL). The resulting mixture was extracted withEtOAc (3×10 mL). The organic layers were combined, dried over Na₂SO₄,filtered and concentrated. The residue obtained was purified by silicagel chromatography (0-10% EtOAc/petroleum ether) to yield ethyl4-(6-chloro-2-methoxypyridin-3-yl)-4-ethylhex-2-enoate as a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₆H₂₂ClNO₃: 312.1[M+H], found:312.1.

Step 2: methyl 4-(6-chloro-2-methoxypyridin-3-yl)-4-ethylhexanoate

To a solution of ethyl4-(6-chloro-2-methoxypyridin-3-yl)-4-ethylhex-2-enoate (300 mg, 0.962mmol) in EtOH (5 mL) charged with H₂ was added PtO₂ (30 mg). Theresulting mixture was stirred at 25° C. overnight. The reaction wasfiltered and concentrated to yield ethyl4-(6-chloro-2-methoxypyridin-3-yl)-4-ethylhexanoate as a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₅H₂₂ClNO₃: 300.1[M+H], found:299.5.

Step 3:5-(2-ethyl-1-hydroxy-2-(2-methoxy-6-(8-(trifluoromethyl)naphthalen-2-yl)pyridin-3-yl)butyl)oxazolidine-2,4-dione

To a solution of ethyl4-(6-chloro-2-methoxypyridin-3-yl)-4-ethylhexanoate (200 mg, 0.667 mmol)in THF (10 mL) was added LDA (1.366 mL) at −78° C. for 1 h. Then3-bromopropanenitrile (137 mg, 1.023 mmol) in THF (5 mL) was added. Theresulting mixture was stirred at 25° C. overnight. After cooling down toroom temperature, the reaction was quenched with H₂O (10 mL). Theresulting mixture was extracted with EtOAc (3×10 mL). The organic layerswere combined, dried over Na₂SO₄, filtered and concentrated. The residueobtained was purified by silica gel chromatography (0-10%EtOAc/petroleum ether) to yield methyl4-(6-chloro-2-methoxypyridin-3-yl)-2-(2-cyanoethyl)-4-ethylhexanoate asa yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₈H₂₅ClN₂O₃: 353.2 [M+H],found: 353.1.

Step 4: methyl2-(3-aminopropyl)-4-(6-chloro-2-methoxypyridin-3-yl)-4-ethylhexanoate

To a rapidly stirred solution of methyl4-(6-chloro-2-methoxypyridin-3-yl)-2-(2-cyanoethyl)-4-ethylhexanoate (90mg, 0.255 mmol) in MeOH (5 mL), was added HCl (0.1 mL), and then PtO₂(10 mg) dropwise under H₂ at 10 atm. The resulting mixture was stirredat 25° C. for 4 h. The reaction was filtered and concentrated to yieldmethyl2-(3-aminopropyl)-4-(6-chloro-2-methoxypyridin-3-yl)-4-ethylhexanoate asa yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₈H₂₉ClN₂O₃: 357.2 [M+H],found: 356.7.

Step 5:3-(2-(6-chloro-2-methoxypyridin-3-yl)-2-ethylbutyl)piperidin-2-one

To a solution of methyl2-(3-aminopropyl)-4-(6-chloro-2-methoxypyridin-3-yl)-4-ethylhexanoate(45 mg, 0.127 mmol) in MeOH (10 mL) was added K₂CO₃ (104 mg, 0.753mmol). The resulting mixture was stirred at 90° C. overnight. Aftercooling down to room temperature, the reaction was quenched with H₂O (10mL). The resulting mixture was extracted with EtOAc (3×10 mL). Theorganic layers were combined, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel chromatography(0-30% EtOAc/petroleum ether) to yield3-(2-(6-chloro-2-methoxypyridin-3-yl)-2-ethylbutyl)piperidin-2-one as ayellow solid.

Mass spectrum (ESI, m/z): Calculated for C₁₇H₂₅ClN₂O₂: 325.2[M+H],found: 324.6.

Step 6:6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-((2-oxopiperidin-3-yl)methyl)pentan-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation with TMSCl/NaI to yield the productas an off-white solid.

¹H NMR (300 MHz, Methanol-d₄), δ: 8.12 (s, 1 H), 7.80 (s, 1 H), 7.52 (s,1 H), 7.25-7.15 (m, 1 H), 6.73-6.71 (m, 1 H), 4.55-4.53 (m, 2 H),3.20-3.12 (m, 2 H), 2.50-2.25 (m, 3 H), 2.24-2.02 (m, 1 H), 1.90-1.80(m, 2 H), 1.79-1.40 (m, 7 H), 1.38-1.25 (m, 1 H), 0.96-0.92 (m, 3 H),0.66-0.61 (m, 3 H). ¹⁹F NMR (300 MHz, Methanol-d₄) δ: −119.24. Massspectrum (ESI, m/z): Calculated for C₂₅H₃₁FN₄O₂: 439.2, found: 439.2[M+H].

Example 89 Compound #1516-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-methyl-1-(5-oxopyrrolidin-2-yl)butan-2-yl)pyridin-2(1H)-one

Step 1: 1-(4-methoxybenzyl)pyrrolidine-2,5-dione

Into a 250 ml round-bottom flask were placed a solution ofpyrrolidine-2,5-dione (3.00 g, 30.276 mmol, 1.00 equiv.) in CH₃CN (100mL), and 1-(chloromethyl)-4-methoxybenzene (5.70 g, 36.331 mmol, 1.20equiv.). K₂CO₃ (4.60 g, 33.304 mmol, 1.10 equiv.) was added. The mixturewas stirred for 16 h at 25° C. The reaction was monitored by LCMS. Theresulting solution was diluted with water (100 mL), then filtered. Thesolid was dried under infrared light to yield1-(4-methoxybenzyl)pyrrolidine-2,5-dione as a white solid.

Mass spectrum (ESI, m/z): Calculated for C₁₂H₁₃NO₃: 220.1 [M+H], found:220.2.

Step 2: 5-hydroxy-1-(4-methoxybenzyl)pyrrolidin-2-one

Into a 100 ml round-bottom flask were placed a solution of1-(4-methoxybenzyl)pyrrolidine-2,5-dione (1.00 g, 4.561 mmol, 1.00equiv.) in THF (30 mL) at −78° C. DIBAL (5 mL, 5.000 mmol, 1.10 equiv.)was added dropwise under nitrogen atmosphere. The mixture was stirredfor 1 hour at −78° C. The reaction was monitored by LCMS. The mixturewas quenched with water and extracted with ethyl acetate (3×50 mL). Theorganic layers were combined, washed with sodium carbonate (aq.) andbrine, dried and concentrated under vacuum. The residue was purified bysilica gel column developed with PE/EA (1/1) to yield5-hydroxy-1-(4-methoxybenzyl)pyrrolidin-2-one as a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₂H₁₅NO₃: 222.1 [M+H], found:222.1.

Step 3: 5-methoxy-1-(4-methoxybenzyl)pyrrolidin-2-one

Into a 50 ml flask were placed a solution of5-hydroxy-1-(4-methoxybenzyl)pyrrolidin-2-one (540 mg, 2.441 mmol, 1.00equiv.) in MeOH (30 mL). HCl (2 mL) was added in several portions at 0°C. The mixture was stirred for 16 hours at room temperature. Thereaction was monitored by LCMS. The mixture was concentrated undervacuum to applied on flash column chromatography silica gel (PE/EA=3/1)to yield 5-methoxy-1-(4-methoxybenzyl)pyrrolidin-2-one (430 mg) ascolorless oil.

Mass spectrum (ESI, m/z): Calculated for C₁₃H₁₇NO₃: 236.1 [M+H], found:236.1.

Step 4: 1-(6-chloro-2-methoxypyridin-3-yl)ethanone

A 250 mL flask was charged with a solution of 2-chloro-6-methoxypyridine(5.00 g, 0.035 mol, 1.00 equiv.) in THF (100 mL) under nitrogenatmosphere. To the mixture was then added tert-butyllithium (33 mL,0.053 mol, 1.30 equiv.) which was added dropwise with stirring at −70°C. The reaction mixture was stirred at −70° C. for 2 h.N-methoxy-N-methylacetamide (4.70 g, 0.046 mol, 1.50 equiv.) was thenadded dropwise. The mixture was stirred for 3.0 h at −78° C. Thereaction progress was monitored by TLC. The reaction was quenched by theaddition of Ammonium chloride aqueous solution and then extracted withethyl acetate, the organic layer was combined and concentrated undervacuum. The residue was applied onto a silica gel column withPE/EA=100/1 to yield 1-(6-chloro-2-methoxypyridin-3-yl)ethanone as awhite solid.

Step 5: 6-chloro-2-methoxy-3-(1-(trimethylsilyloxy)vinyl)pyridine

Into a 40 ml tube were placed a solution of1-(6-chloro-2-methoxypyridin-3-yl)ethanone (700 mg, 3.771 mmol, 1.00equiv.) in tolene (10 mL). Trimethylsilyl trifluoromethanesulfonate(1.26 g, 5.669 mmol, 1.50 equiv.), TEA (770 mg, 7.609 mmol, 2.00 equiv.)was then added. The mixture was stirred for 2 h at 80° C. The reactionwas monitored by LCMS. The mixture was concentrated under vacuum toyield 6-chloro-2-methoxy-3-(1-(trimethylsilyloxy)vinyl)pyridine as ayellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₁H₁₆ClNO₂Si: 258.1[M+H],found: 258.2.

Step 6: 6-chloro-2-methoxy-3-(1-(trimethylsilyloxy)vinyl)pyridine

Into a 50 ml flask were placed a solution of6-chloro-2-methoxy-3-(1-(trimethylsilyloxy)vinyl)pyridine (700 mg, 2.715mmol, 1.00 equiv.) in CH₃CN (10 mL), and a solution of5-methoxy-1-(4-methoxybenzyl)pyrrolidin-2-one (700 mg, 2.975 mmol, 1.10equiv.) in CH₃CN (10 mL) was added. Triisopropylsilyltrifluoromethanesulfonate (1.66 g, 5.431 mmol, 2.00 equiv.) was thenadded. The mixture was stirred for 16 h at 25° C. The mixture wasconcentrated under vacuum. The residue was purified by chromatogram onsilica gel with ethyl acetate/petroleum ether (1:6) to yield5-(2-(6-chloro-2-methoxypyridin-3-yl)-2-oxoethyl)-1-(4-methoxybenzyl)pyrrolidin-2-oneas yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₀H₂₁ClN₂O₄: 411.1 [M+Na],found: 411.3.

Step 7:5-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-2-oxoethyl)-1-(4-methoxybenzyl)-pyrrolidin-2-one

To a solution of5-(2-(6-chloro-2-methoxypyridin-3-yl)-2-oxoethyl)-1-(4-methoxybenzyl)pyrrolidin-2-one(1.50 g, 3.858 mmol, 1.00 equiv.) in ethylene glycol dimethyl ether (30ml) was added1-ethyl-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(1.35 g, 4.635 mmol, 1.20 equiv.), sodium carbonate (822 mg, 7.756 mmol,2.00 equiv.), TBAB (1.25 g, 3.864 mmol, 1.00 equiv.), water (10 mL),Pd(PPh₃)₄(134 mg, 0.116 mmol, 0.03 equiv.). The reaction mixture wasstirred overnight at 90° C. under nitrogen atmosphere. The mixture wasextracted with ethyl acetate (3×50 mL). The organic layers werecombined, washed with sodium carbonate (aq.) and brine, dried andconcentrated under vacuum. The residue was purified by chromatogram onsilica gel with ethyl acetate/petroleum ether (1:1) to yield5-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-2-oxoethyl)-1-(4-methoxybenzyl)pyrrolidin-2-oneas black solid.

Mass spectrum (ESI, m/z): Calculated for C₂₉H₂₉FN₄O₄: 539.2[M+Na],found: 539.4.

Step 8:5-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-2-hydroxy-3-methylbutyl)-1-(4-methoxybenzyl)pyrrolidin-2-one

Into a 100 ml flask were placed a solution of5-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-2-oxoethyl)-1-(4-methoxybenzyl)pyrrolidin-2-one(1.60 g, 3.097 mmol, 1.00 equiv.) in THF (30 mL). Isopropylmagnesiumchloride (2.33 ml, 4.66 mmol, 1.50 equiv.) was added at −78° C. undernitrogen atmosphere. The mixture was stirred for 6 h at 0° C. Thereaction was monitored by LCMS. The reaction was quenched with MeOH andconcentrated under vacuum and extracted with ethyl acetate (3×50 mL).The organic layers were combined, washed with sodium carbonate (aq.) andbrine, dried and concentrated under vacuum. The residue was purified bychromatogram on silica gel with DCM/MeOH (20/1) to yield5-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-2-hydroxy-3-methylbutyl)-1-(4-methoxybenzyl)pyrrolidin-2-oneas brown solid.

Mass spectrum (ESI, m/z): Calculated for C₃₂H₃₇FN₄O₄: 583.3 [M+Na],found: 583.4.

Step 9:5-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbut-1-enyl)pyrrolidin-2-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation with TMSCl/NaI to yield the productas a yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₇FN₄O₂: 445.2[M+Na],found: 445.4.

Step 10:6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-methyl-1-(5-oxopyrrolidin-2-yl)butan-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation to yield the product as a whitesolid.

¹H NMR (300 MHz, CD₃OD) δ: 8.13 (s, 1H), 7.80 (s, 1H), 7.55 (d, J=7.2Hz, 1H), 7.16-7.21 (m, 1H), 6.78 (d, J=7.2 Hz, 1H), 4.48-4.60 (m, 2H),3.35-3.50 (m, 1H), 2.73-2.90 (m, 1H), 2.11-2.35 (m, 3H), 1.60-1.80 (m,3H), 1.80-2.00 (m, 1H), 1.45-1.53 (m, 3H), 1.02-1.04 (m, 3H), 0.78-0.90(m, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −119.122. Mass spectrum (ESI, m/z):Calculated for C₂₃H₂₇FN₄O₂: 411.2 [M+H], found: 411.2.

Example 90 Compound #763-(1-(1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

Step 1:3-(1-(1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridine

Into 40 mL vial,2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanal(50 mg, 0.148 mmol, 1 eq.) was dissolved (7M) NH₃ in methanol, and thenoxalaldehyde (17.2 mg, 0.296 mmol, 2.0 eq.) was added. The reactionmixture was stirred for 16 h at 35° C. The mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1/1) to yield3-(1-(1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridineas an off-white solid.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₂FN₃O, 376.2 (M+H), found376.2.

Step 2:3-(1-(1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

Into a 40-mL vial, were placed3-(1-(1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridine(40 mg, 0.107 mmol, 1.00 equiv.), chlorotrimethylsilane (34.6 mg, 0.318mmol, 3.0 equiv.), sodium iodide (48 mg, 0.320 mmol, 3.0 equiv.), MeCN(10 mL). The resulting solution was stirred overnight at 25° C. Theresulting solution was diluted with methanol (1 mL).

The resulting solution was concentrated under vacuum. The residue (40mg) was purified by Prep-HPLC with the following conditions(1#waters2767-5): Column, SunFire Prep C18,19*150 mm 5 umH PrepC-001(T)18600256819513816414 04; mobile phase, Phase A:water with 0.05%NH₄HCO₃ Phase B:CH₃CN (25% CH₃CN up to 45% in 10 min, up to 100% CH₃CNin 0.1 min, hold 100% in 1.9 min, down to 25% CH₃CN in 0.1 min, hold 25%in 1.9 min); Detector, UV220&254 nm to yield3-(1-(1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-oneas a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.34 (s, 1H), 7.98-8.01 (m, 1H), 7.69-7.80(m, 3H), 7.45-7.52 (m, 1H), 7.20-7.26 (m, 1H), 6.90 (s, 2H), 6.74 (d,J=7.5 Hz, 1H), 3.93 (d, J=10.8 Hz, 1H), 2.55-2.67 (m, 1H), 0.90 (d,J=6.6 Hz, 3H), 0.82 (d, J=6.6 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ:−122.45. Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₀FN₃O, 362.2(M+H), found 362.2.

Example 91 Compound #140 3-(1-(1H-imidazol-2-yl)-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

Step 1: (E)-methyl3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpent-2-enoate

Into a 25-mL round-bottom flask were placed a solution of ethyl2-(trimethylsilyl)acetate (2.53 g, 15.784 mmol, 2.00 equiv.) in THF at−78° C. under nitrogen atmosphere. To the mixture was then added lithiumbis(trimethylsilyl)amide (15.8 mL, 15.8 mmol, 2.00 equiv.), which wasadded dropwise with stirring at −78° C. The reaction mixture was stirredat −78° C. for 30 min. A solution of1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-one(2.4 g, 7.422 mmol, 1.00 equiv.) in THF was then added dropwise. Themixture was stirred for 10 min at −78° C. The reaction progress wasmonitored by LCMS. The reaction was quenched by the addition ofmethanol. The reaction mixture was concentrated under vacuum. Theresidue was purified by thin layer chromatography developed with PE/EA(6:1) to yield (E)-methyl3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpent-2-enoateas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₂FNO₃, 380.2 (M+H), found380.1.

Step 2: Methyl3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentanoate

Into a 25 mL round-bottom flask were placed a solution of (E)-methyl3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpent-2-enoate(2.23 g, 5.877 mmol, 1.00 equiv.) in MeOH and then PtO₂ (466 mg, 2.052mmol, 0.35 equiv.) was added. The mixture was stirred overnight at roomtemperature under an atmosphere of hydrogen. PtO₂ was filtered out. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:15) to yieldmethyl3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentanoateas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₄FNO₃, 382.2 (M+H), found382.1.

Step 3:3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentan-1-ol

Into 50 mL round-bottom flask, methyl3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentanoate(50 mg, 0.131 mmol, 1 equiv.) was dissolved in THF (20 mL). LAH (10 mg,0.263 mmol, 2 equiv.) was then added. The mixture was stirred for 1 h at25° C. The mixture was quenched with Na₂SO₄.10H₂O and filtered out. Theorganic layer was concentrated under vacuum. The residue was appliedonto a silica gel column with PE/EA (6:1) to yield3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentan-1-olas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₄FNO₂, 354.2 (M+H), found354.1.

Step 4:3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentanal

Into 50-mL round-bottom flask,3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentan-1-ol(40 mg, 0.113 mmol, 1 equiv.) was dissolved in THF (20 mL), and thenDess-Martin periodinane (96 mg, 0.226 mmol, 2 equiv.) was added. Themixture was stirred at 3 h at 25° C. and quenched with Na₂S₂O₃—NaHCO₃solution. The mixture was extracted with EA. The organic layer wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with PE/EA (6:1) to yield3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentanalas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂FNO₂, 352.2 (M+H), found352.1.

Step 5:3-(1-(1H-imidazol-2-yl)-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 90 by condensation of3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentanaland oxalaldehyde followed by demethylation of3-(1-(1H-imidazol-2-yl)-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridinewith TMSCl/NaI in CH₃CN to yield the products as an off-yellow solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.37 (s, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.82(d, J=7.2 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.52-7.57 (m, 1H), 7.41 (d,J=7.2 Hz, 1H), 7.27-7.31 (m, 1H), 6.83 (s, 2H), 6.69 (d, J=7.2 Hz, 1H),3.11-3.24 (m, 3H), 2.05-2.21 (m, 1H), 1.08 (d, J=6.8 Hz,3H), 0.94 (d,J=6.8 Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −124.56. Mass spectrum (ESI,m/z): Calculated for C₂₃H₂₂FN₃O, 376.2 (M+H), found 376.2.

Example 92 Compound #1316-(8-Fluoronaphthalen-2-yl)-3-(2-methyl-1-(5-methyl-1H-imidazol-2-yl)propyl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 90 by condensation of2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanaland 2-oxopropanal followed by demethylation of6-(8-fluoronaphthalen-2-yl)-2-methoxy-3-(2-methyl-1-(5-methyl-1H-imidazol-2-yl)propyl)pyridinewith TMSCl/NaI in CH₃CN to yield a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.35 (s, 1H), 8.02 (d, J=9.0 Hz, 1H), 7.80(d, J=8.7 Hz, 1H), 7.70-7.74 (m, 2H), 7.46-7.53 (m, 1H), 7.21-7.27 (m,1H), 6.75 (d, J=7.5 Hz, 1H), 6.59 (s, 1H), 3.85 (d, J=11.1 Hz Hz, 1H),2.54-2.66 (m, 1H), 2.15 (s, 3H), 0.89 (d, J=6.6 Hz, 3H), 0.85 (d, J=6.3Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −124.47. Mass spectrum (ESI, m/z):Calculated for C₂₃H₂₂FN₃O, 376.2 (M+H), found 376.1.

Example 93 Compound #673-(1-(4,5-Dimethyl-1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 90 by condensation of2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanaland 2,3-butanedione followed by demethylation of3-(1-(4,5-dimethyl-1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridinewith TMSCl/NaI in CH₃CN to yield an off-white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.40 (s, 1 H), 8.06-8.08 (m, 1 H), 7.75-7.85(m, 3 H), 7.53-7.58 (m, 1 H), 7.27-7.31 (m, 1 H), 6.84 (d, J=7.2 Hz, 1H), 3.96 (d, J=8.4 Hz, 1 H), 2.73-2.79 (m, 1 H), 2.23 (s, 6 H), 1.02 (d,J=6.4 Hz, 3 H), 0.95 (d, J=6.4 Hz, 3 H). ¹⁹F NMR (400 MHz, CD₃OD) δ:−75.00, −124.48.

Mass spectrum (ESI, m/z): Calculated forC_(27.98)H_(25.99)F_(6.97)N₃O_(4.98), 390.2 (M−1.99CF₃COOH+H), found390.2.

Example 94 Compound #823-(1-(1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)-5-methylpyridin-2(1H)-one

Step 1:2-(5-bromo-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanal

Into a 100-mL round bottle maintained with an inert atmosphere ofnitrogen, were placed2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanal(200 mg, 0.59 mmol, 1 equiv.), NBS (126 mg, 0.71 mmol, 1.2 equiv.), DMF(5 mL). The resulting solution was stirred for 3 h at 60° C. The mixturewas concentrated under vacuum. The residue was purified purified by TLCwith ethyl acetate/petroleum ether (1:6) to yield2-(5-bromo-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanalas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₁₉BrFNO₂, 416.3[M+H],416.0.

Step 2:2-(6-(8-fluoronaphthalen-2-yl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanal

Into a 40-mL vial purged and maintained with an inert atmosphere ofnitrogen, were placed2-(5-bromo-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanal(200 mg, 0.48 mmol, 1 equiv.), DMF (5 mL), PdCl₂ (5 mg, 0.028 mmol, 0.05equiv.), (o-tol)₃P (14 mg, 0.046 mmol, 0.1 equiv.), tetramethylstannane(173 mg, 0.96 mmol, 2 equiv.). The resulting solution was stirred with16 h at 100° C. The mixture was concentrated under vacuum. The residuewas purified purified by TLC with ethyl acetate/petroleum ether (1:15)to yield2-(6-(8-fluoronaphthalen-2-yl)-2-methoxy-5-methylpyridin-3-yl)-3-methylbutanalas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂FNO₂, 352.2 [M+H], 352.1.

Step 3:3-(1-(1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)-5-methylpyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 90 by condensation of2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanaland oxalaldehyde followed by demethylation of3-(1-(1H-imidazol-2-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)-2-methoxy-5-methylpyridine with TMSCl/NaI in CH₃CN to yield a white solid.

¹H NMR (300 MHz,CD₃OD) δ: 8.11 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.74 (d,J=8.4 Hz, 1H), 7.66 (s, 1H), 7.49-7.51 (m, 2H), 7.23-7.28 (m, 1H), 7.06(s, 2H), 3.93 (d, J=11.1 Hz, 1H), 3.65-2.72 (m, 1H), 2.09 (s, 3H), 0.94(d, J=6.6 Hz, 3H), 0.85 (d, J=6.6 Hz, 3H). ¹⁹F NMR (300 MHz,CD₃OD) δ:−76.95, −124.96. Mass spectrum (ESI, m/z): Calculated forC_(23.64)H_(22.32)F_(1.96)N₃O_(1.64), 376.2 [M−0.32CF₃COOH+H], found376.1.

Example 95 Compound #3073-(2-(1H-Imidazol-2-yl)-3-methylbutyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

Step 1:2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutan-1-ol

Into a 25 mL round-bottom flask were placed a solution of ethyl2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutanoate(50 mg, 0.126 mmol, 1 equiv.) in THF (2 mL) at 0° C., and thenlithiumaluminiumtetrahydride (10 mg, 0.263 mmol, 2 equiv.) was added inseveral portions. The mixture was stirred for 1 h. The mixture wasquenched by MeOH and concentrated under vacuum. The residue product waspurified by chromatogram on silica gel with ethyl acetate/petroleumether (10:1) to yield2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutan-1-olas alight yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₄FNO₂, 354.2 (M+H), found354.1.

Step 2:2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutanal

Into a 25-mL round-bottom flask, were placed2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutan-1-ol(40 mg, 0.113 mmol, 1 equiv.), CH₂Cl₂ (2 mL).(1,1,1-Triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (126 mg, 0.297mmol, 3 equiv.) was then added in portions at room temperature. Theresulting solution was stirred 1 h at room temperature. The reactionprogress was monitored by TLC/LCMS (PE:EA=6:1). The reaction was thenquenched by Na₂S₂O₃/NaHCO₃/H₂O. The reaction was extracted with ethylacetate and dried over anhydrous sodium sulfate and concentrated undervacuum. The residue product was purified by chromatogram on silica gelwith ethyl acetate/petroleum ether (10:1) to yield2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutanalas a colorless oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂FNO₂, 352.2 (M+H), found352.2.

Step 3:3-(2-(1H-imidazol-2-yl)-3-methylbutyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 90 by condensation of2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutanaland oxalaldehyde followed by demethylation of3-(2-(1H-imidazol-2-yl)-3-methylbutyl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridinewith TMSCl/NaI in CH₃CN to yield a light yellow solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.34 (s, 1H), 8.04 (d, J=8.8 Hz, 1H),7.75-7.79 (m, 2H), 7.51-7.57 (m, 1H), 7.26-7.31 (m, 1H), 7.15 (d, J=7.2Hz, 1H), 6.91 (s, 2H), 6.54 (d, J=7.2 Hz, 1H), 3.21-3.26 (m, 1H),3.04-3.10 (m, 1H), 2.77-2.84 (m, 1H), 2.03-2.11 (m, 1H), 1.11 (d, J=6.8Hz, 3H), 0.98 (d, J=6.8 Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −124.60.Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₂FN₃O, 376.2 (M+H), found376.2.

Example 96 Compound #503-(3-(1H-imidazol-2-yl)pentan-3-yl)-6-(6,8-difluoronaphthalen-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 90 by condensation followed by demethylation to yield theproduct as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.39 (s, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.92(d, J=7.8 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.54 (d, J=7.2 Hz, 1H),7.21-7.31 (m, 1H), 6.93 (s, 2H), 6.82 (d, J=7.5 Hz, 1H), 2.44-2.49 (m,2H), 2.12-2.17 (m, 2H), 0.72 (t, J=7.2 Hz, 6H). ¹⁹F NMR (300 MHz, CD₃OD)δ: −111.96, −119.52. Mass spectrum (ESI, m/z): Calculated ForC₂₃H₂₁F₂N₃O, 394.2 [M+H], found 394.1.

Example 97 Compound #313-(3-(1H-imidazol-2-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 90 by condensation followed by demethylation to yield theproduct as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 8.12 (s, 1H), 7.77 (s, 1H), 7.67 (d, J=7.6 Hz,1H), 7.17 (d, J=10.2 Hz, 1H), 6.90 (s, 2H), 6.76 (d, J=7.6 Hz, 1H),4.49-4.55 (m, 2H), 2.40-2.49 (m, 2H), 2.06-2.15 (m, 2H), 1.49-1.52 (m,3H), 0.67-0.71 (m, 6H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −119.22. Massspectrum (ESI, m/z): Calculated for C₂₂H₂₄FN₅O, 394.2 [M+H], found394.3.

Example 98 Compound #203-(3-((1H-imidazol-2-yl)methyl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 90 by condensation followed by demethylation to yield theproduct as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.15 (s, 1H), 7.82 (s, 1H), 7.37 (d, J=7.5Hz, 1H), 7.20 (d, J=11.1 Hz, 1H), 6.85 (s, 2H), 6.67 (d, J=7.5 Hz, 1H),4.56-4.58 (m, 2H), 3.33-3.36 (m, 2H), 2.00-2.04 (m, 2H), 1.80-1.84 (m,2H), 1.53-1.57 (m, 3H), 0.83-0.88 (m, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ:−119.23. Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₆FN₅O, 408.2[M+H], found 408.0.

Example 99 Compound #1386-(8-Fluoronaphthalen-2-yl)-3-(2-methyl-1-(4H-1,2,4-triazol-3-yl)propyl)pyridin-2(1H)-one

Step 1:2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanamide

Into a 50-mL round-bottom flask, were placed2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanoicacid (50 mg, 0.141 mmol, 1.0 equiv.), NH₄Cl (15 mg, 0.278 mmol, 2.0equiv.), HATU (106 mg, 0.279 mmol, 2.0 equiv.), DIPEA (36 mg, 0.279mmol, 2.0 equiv.), DMF (2.5 mL), DCM (2.5 mL). The resulting solutionwas stirred overnight at room temperature. The reaction progress wasmonitored by LCMS. The resulting mixture was concentrated under vacuum.The residue was applied TLC with DCM:MeOH=10:1 to yield2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanamideas a brown oil.

Mass spectrum (ESI, m/z): Calculated For C₂₁H₂₁FN₂O₂, 353.2 (M+H), found353.0.

Step 2:6-(8-fluoronaphthalen-2-yl)-2-methoxy-3-(2-methyl-1-(4H-1,2,4-triazol-3-yl)propyl)pyridine

Into a 50-mL round-bottom flask, were placed2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanamide(60 mg, 0.170 mmol, 1.0 equiv.), DMF-DMA (5 mL). The resulting solutionwas stirred 2.0 h at 100° C. Then the resulting mixture was concentratedunder vacuum. AcOH (5 mL) and NH₂NH₂ (0.5 mL) were then added. Theresulting solution was stirred 1.0 h at 90° C. The reaction progress wasmonitored by LCMS. The resulting mixture was concentrated under vacuum.The residue was applied TLC with PE:EA=2:1 to yield6-(8-fluoronaphthalen-2-yl)-2-methoxy-3-(2-methyl-1-(4H-1,2,4-triazol-3-yl)propyl)pyridine as a brown oil.

Mass spectrum (ESI, m/z): Calculated For C₂₂H₂₁FN₄O, 377.2 (M+H), found377.0.

Step 3:6-(8-fluoronaphthalen-2-yl)-3-(2-methyl-1-(4H-1,2,4-triazol-3-yl)propyl)pyridin-2(1H)-one

Into a 50-mL round-bottom flask were placed6-(8-fluoronaphthalen-2-yl)-2-methoxy-3-(2-methyl-1-(4H-1,2,4-triazol-3-yl)propyl)pyridine(30 mg, 0.080 mmol, 1.0 equiv.), CH₃CN (5 mL), NaI (36 mg, 0.24 mmol,3.0 equiv.), TMSCl (26 mg, 0.239 mmol, 3.0 equiv.). The resultingsolution was stirred overnight at 30° C. The reaction progress wasmonitored by LCMS. The reaction was then quenched by the addition ofMeOH. The resulting mixture was concentrated under vacuum and purifiedby Prep-HPLC with the following conditions (16#-Waters 2767-5): Column,SunFire Prep C18,19*100 mm, 5 um; mobile phase, Water with 0.05% NH₄HCO₃and CH₃CN (25% CH₃CN up to 35% in 10 min, up to 100% in 0.1 min, hold100% in 0.9 min, down to 20% in 0.1 min, hold 20% in 1.4 min); Detector,UV 220 & 254 nm to yield6-(8-fluoronaphthalen-2-yl)-3-(2-methyl-1-(4H-1,2,4-triazol-3-yl)propyl)pyridin-2(1H)-oneas a white solid.

¹H NMR (300 MHz,CD₃OD) δ: 8.36 (s, 1H), 7.99-8.08 (m, 2H), 7.78-7.84 (m,2H), 7.72 (d, J=8.4 Hz, 1H), 7.46-7.53 (m, 1H), 7.21-7.27 (m, 1H), 6.76(d, J=7.5 Hz, 1H), 4.26 (d, J=10.2 Hz, 1H), 2.48-2.61 (m, 1H), 0.95 (d,J=6.9 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H). 19F NMR (300 MHz,CD₃OD) δ:−124.42.

Mass spectrum (ESI, m/z): Calculated For C₂₁H₁₉FN₄O, 363.2 (M+H), found363.0.

Example 100 Compound #1396-(8-Fluoronaphthalen-2-yl)-3-(4-isopropyl-2-(methylthio)-5-oxo-4,5-dihydro-1H-imidazol-4-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 99 by condensation of3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentanamide and DMF-DMA followed by demethylation of6-(8-fluoronaphthalen-2-yl)-2-methoxy-3-(3-methyl-1-(1H-1,2,4-triazol-5-yl)butan-2-yl)pyridinewith TMSCl/NaI in CH₃CN to yield a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.37 (s, 1H), 8.00-8.06 (m, 2H), 7.82 (d,J=8.4 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.51-7.57 (m, 1H), 7.39 (d, J=7.2Hz, 1H), 7.26-7.38 (m, 1H), 6.68 (d, J=7.2 Hz, 1H), 3.21-3.50 (m, 3H),2.19-2.28 (m, 1H), 1.10 (d, J=6.4 Hz, 3H), 0.97 (d, J=6.0 Hz, 3H). ¹⁹FNMR (400 MHz, CD₃OD) δ: −152.3. Mass spectrum (ESI, m/z): Calculated forC₂₂H₂₁FN₄O_(, 377.2) (M+H), found 377.1.

Example 101 Compound #3096-(8-Fluoronaphthalen-2-yl)-3-(3-methyl-2-(4H-1,2,4-triazol-3-yl)butyl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 99 by condensation of2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutanamideand DMF-DMA followed by demethylation of6-(8-fluoronaphthalen-2-yl)-2-methoxy-3-(3-methyl-2-(4H-1,2,4-triazol-3-yl)butyl)pyridinewith TMSCl/NaI in CH₃CN to yield a light yellow solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.32 (s, 1H), 8.07 (s, 1H), 8.04 (d, J=7.2Hz, 1H), 7.73-7.75 (m, 2H), 7.48-7.59 (m, 1H), 7.20-7.30 (m, 1H), 7.17(d, J=6.8 Hz, 1H), 6.54 (d, J=7.2 Hz, 1H), 3.20-3.30 (m, 2H), 2.79-2.88(m, 1H), 2.05-2.15 (m, 1H), 1.10 (d, J=6.8 Hz, 3H), 0.87 (d, J=6.8 Hz,3H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −76.95, −124.59. Mass spectrum (ESI,m/z): Calculated for C_(22.16)H_(21.08)F_(1.24)N₄O_(1.16), 377.2(M−0.08C₂HF₃O₂+H), found 377.2.

Example 102 Compound #223-(3-(4H-1,2,4-triazol-3-yl)pentan-3-yl)-6-(4-ethyl-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 99 by condensation followed by demethylation to yield theproduct as an off-white solid.

¹H NMR (300 MHz, CD₃OD) δ 7.81 (s, 1H), 7.62 (d, J=7.2 Hz, 1H),6.89-6.75 (m, 2H), 6.55 (d, J=7.5 Hz, 1H), 4.24-4.27 (m, 2H), 3.35-3.47(m, 4H), 2.34-2.46 (m, 2H), 1.89-2.12 (m, 2H), 1.12-1.17 (m, 3H),0.54-0.71 (m, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ −138.25. Mass spectrum(ESI, m/z): Calculated for C₂₂H₂₆FN₅O₂, 412.2 [M+H], found 412.4.

Example 103 Compound #216-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(5-methyl-4H-1,2,4-triazol-3-yl)pentan-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 99 by condensation followed by demethylation to yield theproduct as a white solid.

¹H NMR (300 MHz, CD₃OD) δ 8.09 (s, 1H), 7.75 (s, 1H), 7.67-7.69 (m, 1H),7.15 (d, J=11.1 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 4.47-4.54 (m, 2H),2.29-2.47 (m, 5H), 1.99-2.18 (m, 2H), 1.46-1.51 (m, 3H), 0.66-0.71 (m,6H). ¹⁹F NMR (300 MHz, CD₃OD) δ −119.17. Mass spectrum (ESI, m/z):Calculated for C₂₂H₂₅FN₆O, 409.2 [M+H], found 409.0.

Example 104 Compound #333-(3-(4H-1,2,4-triazol-3-yl)pentan-3-yl)-6-(5,7-difluoronaphthalen-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 99 by condensation followed by demethylation to yield theproduct as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.77 (s, 1H), 8.18-8.76 (m, 2H), 7.56 (t,J=8.7 Hz, 2H), 7.28 (d, J=7.2 Hz, 1H), 7.25 (t, J=9.0 Hz, 1H), 6.90 (d,J=7.5 Hz, 1H), 2.43-2.55 (m, 2H), 2.08-2.20 (m, 2H), 0.78 (t, J=7.5 Hz,6H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −77.23, −112.45, −120.15. Mass spectrum(ESI, m/z): Calculated for C_(23.84)H_(20.92)F_(4.76)N₄O_(2.84), 395.2[M−0.92CF₃COOH+H], found 395.1.

Example 105 Compound #53-(3-(4H-1,2,4-triazol-3-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one-one

The title compound was prepared according to the procedure as describedin Example 99 by condensation followed by demethylation to yield theproduct as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 7.89-7.94 (m, 1H), 7.78 (s, 1H),7.72 (d, J=7.6 Hz, 1H), 7.18 (d, J=10.0 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H),4.50-4.55 (m, 2H), 2.43-2.50 (m, 2H), 2.13-2.16 (m, 2H), 1.51-1.52 (m,3H), 0.79-0.85 (m, 6H). ¹⁹F NMR (400 MHz, CD₃OD) δ −119.17. Massspectrum (ESI, m/z): Calculated for C₂₁H₂₃FN₆O, 395.2 [M+H], found395.2.

Example 106 Compound #393-(3-(4H-1,2,4-triazol-3-yl)pentan-3-yl)-6-(6,8-difluoronaphthalen-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 99 by condensation followed by demethylation to yield theproduct as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.73 (s, 1H), 8.39 (s, 1H), 8.05 (d, J=8.7Hz, 1H), 7.82-7.90 (m, 2H), 7.51 (d, J=9.3 Hz, 1H), 7.26-7.49 (m, 1H),6.88 (d, J=7.5 Hz, 1H), 2.44-2.51 (m, 2H), 2.09-2.17 (m, 2H), 0.77 (t,J=7.2 Hz, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −77.30, −111.45, −119.40.Mass spectrum (ESI, m/z): Calculated forC_(25.02)H_(21.51)F_(6.53)N₄O_(4.02), 428.1 [M−0.84CF₃COOH+H], found395.1.

Example 107 Compound #2793-(3-((4H-1,2,4-triazol-3-yl)methyl)pentan-3-yl)-6-(6,8-difluoronaphthalen-2-yl)pyridin-2(3H)-one

The title compound was prepared according to the procedure as describedin Example 99 by condensation followed by demethylation to yield theproduct as a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.39 (s, 1H), 7.87-8.01 (m, 3H), 7.48-7.50(m, 1H), 7.36 (d, J=7.5 Hz, 1H), 7.22-7.27 (m, 1H), 6.66 (d, J=7.5 Hz,1H), 3.48 (s, 2H), 2.01-2.08 (m, 2H), 1.77-1.82 (m, 2H), 0.85 (t, J=7.4Hz, 6H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −111.99, −119.49. Mass spectrum(ESI, m/z): Calculated for C₂₃H₂₂F₂N₄O, 409.2 [M+H], found 409.1.

Example 108 Compound #153-(3-((4H-1,2,4-triazol-3-yl)methyl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 99 by condensation followed by demethylation to yield theproduct as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.15 (s, 1H), 7.95-8.05 (m, 1H), 7.82 (s,1H), 7.37 (d, J=7.5 Hz, 1H), 7.17-7.22 (m, 1H), 7.66 (d, J=7.5 Hz, 1H),4.53-4.60 (m, 2H), 3.48 (s, 2H), 2.04-2.08 (m, 2H), 1.81-1.86 (m, 2H),1.52-1.57 (m, 3H), 0.85-0.90 (m, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ:−119.24.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₅FN₆O, 409.2 [M+H], found409.1.

Example 109 Compound #26 and #27 and #246-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(4-methyl-4H-1,2,4-triazol-3-yl)pentan-3-yl)pyridin-2(1H)-oneand6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(1-methyl-1H-1,2,4-triazol-3-yl)pentan-3-yl)pyridin-2(1H)-oneand6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(2-methyl-2H-1,2,4-triazol-3-yl)pentan-3-yl)pyridin-2(1H)-one

Into a 50-mL round bottle, to a solution of6-(5-(3-(4H-1,2,4-triazol-3-yl)pentan-3-yl)-6-methoxypyridin-2-yl)-1-ethyl-4-fluoro-1H-indazole(100 mg, 0.245 mmol, 1.00 equiv.) in THF (10 mL), was added NaH (15 mg,0.367 mmol, 1.50 equiv.) with stirring at 0° C., followed by addition ofiodomethane (52 mg, 0.367 mmol, 1.50 equiv.). The reaction mixture wasstirred for 2 h at 20° C.

The mixture was quenched by the addition of H₂O, extracted with EA, theorganic layers was concentrated under vacuum. The residue was purifiedby TLC with ethyl acetate/petroleum ether (1:2). The collected fractionswere combined and concentrated under vacuum to yield1-ethyl-4-fluoro-6-(6-methoxy-5-(3-(4-methyl-4H-1,2,4-triazol-3-yl)pentan-3-yl)pyridin-2-yl)-1H-indazoleas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₇FN₆O, 423.1 [M+H], found423.3.

The title compounds were then prepared according to the procedure asdescribed in Example 1 step 5 by demethylation to yield

6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(4-methyl-4H-1,2,4-triazol-3-yl)pentan-3-yl)pyridin-2(1H)-oneas a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.28 (s, 1H), 8.13 (s, 1H),7.82 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.19-7.23 (m, 1H), 6.85 (d, J=7.6Hz, 1H), 4.51-4.56 (m, 2H), 3.36 (s, 3H), 2.40-2.49 (m, 2H), 2.15-2.25(m, 2H), 1.51 (t, J=7.2 Hz, 3H), 0.69-0.73 (m, 6H). ¹⁹F NMR (400 MHz,CD₃OD) δ −119.08. Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₅FN₆O,409.2 [M+H], found 409.0.

6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(1-methyl-1H-1,2,4-triazol-3-yl)pentan-3-yl)pyridin-2(1H)-oneas a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 7.81 (s, 2H),7.76-7.85 (m, 1H), 7.19-7.23 (m, 1H), 6.85-6.87 (m, 1H), 4.51-4.57 (m,2H), 3.62 (s, 3H), 2.37-2.46 (m, 2H), 2.14-2.23 (m, 2H), 1.51 (t, J=7.2Hz, 3H), 0.67-0.74 (m, 6H). ¹⁹F NMR (400 MHz, CD₃OD) δ −119.11. Massspectrum (ESI, m/z): Calculated for C₂₂H₂₅FN₆O, 409.2 [M+H], found409.0.

and6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(2-methyl-2H-1,2,4-triazol-3-yl)pentan-3-yl)pyridin-2(1H)-oneas a white solid. ¹H NMR (400 MHz, CD₃OD) δ: 8.25 (s, 1H), 8.12-8.13 (m,1H), 7.76-7.82 (m, 2H), 7.15-7.23 (m, 1H), 6.75-6.84 (m, 1H), 4.51-4.56(m, 2H), 3.62-3.88 (m, 3H), 2.37-2.46 (m, 2H), 2.06-2.21 (m, 2H), 1.51(t, J=7.2 Hz, 3H), 0.67-0.77 (m, 6H). ¹⁹F NMR (400 MHz, CD₃OD) δ:−119.08. Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₅FN₆O, 409.2[M+H], found 409.0.

Example 110 Compound #363-(3-(4H-1,2,4-triazol-3-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-5-fluoropyridin-2(1H)-one

Step 1: Methyl 6-chloro-5-fluoro-2-methoxynicotinatel

Into a 250-mL vial maintained with an inert atmosphere of nitrogen, to asolution of methyl 2,6-dichloro-5-fluoronicotinate (2.00 g, 9.100 mmol,1.00 equiv.) in DCE (50 mL) was added NaOMe (0.74 g, 13.600 mmol, 1.50equiv.). The reaction mixture was stirred for 16 h at 70° C. The mixturewas concentrated under vacuum. The residue was purified by silica gelwith ethyl acetate/petroleum ether (8:92). The collected fractions werecombined and concentrated under vacuum to methyl6-chloro-5-fluoro-2-methoxynicotinatel as white solid.

Mass spectrum (ESI, m/z): Calculated for C₈H₇ClFNO₃, 220.0 [M+H], found220.1.

Step 2: (6-chloro-5-fluoro-2-methoxypyridin-3-yl)methanol

Into a 250-mL round bottle, to a solution of methyl6-chloro-5-fluoro-2-methoxynicotinatel (2.20 g, 10.000 mmol, 1.00equiv.) in DCM (100 mL) was added DIBAL (20 mL, 20.000 mmol, 2.00equiv.) with stirring at −78° C. The mixture was stirred for 2 h at 20°C. The mixture was quenched by the addition of NH₄Cl (aq), extractedwith DCM, the organic layers was concentrated under vacuum. The residuewas purified by silica gel with ethyl acetate/petroleum ether (15:85).The collected fractions were combined and concentrated under vacuum toyield (6-chloro-5-fluoro-2-methoxypyridin-3-yl)methanol as white solid.

Mass spectrum (ESI, m/z): Calculated for C₇H₇ClFNO₂, 192.0 [M+H], found192.1.

Step 3: 6-chloro-5-fluoro-2-methoxynicotinaldehyde

Into a 250-mL round bottle, to a solution of(6-chloro-5-fluoro-2-methoxypyridin-3-yl)methanol (1.90 g, 9.900 mmol,1.00 equiv.) in DCM (100 mL), was added DMP (12.60 g, 30.000 mmol, 3.00equiv.) with stirring at 0° C. The mixture was stirred for 2 h at 20° C.The mixture was quenched by the addition of Na₂S₂O₃ (aq), extracted withDCM, the organic layers was concentrated under vacuum. The residue waspurified by silica gel with ethyl acetate/petroleum ether (10:90). Thecollected fractions were combined and concentrated under vacuum to yield\6-chloro-5-fluoro-2-methoxynicotinaldehyde as yellow oil.

¹H NMR (400 MHz, DMSO-d₆) δ 10.14 (d, J=2.6 Hz, 1H), 8.18 (d, J=7.7 Hz,1H), 4.02 (s, 3H).

Step 4: 2-(6-chloro-5-fluoro-2-methoxypyridin-3-yl)acetonitrile

Into a 250-mL round bottle maintained with an inert atmosphere ofnitrogen, were placed DME (100 mL), t-BuOK (17 mL, 17.000 mmol, 2.20equiv.), toluenesulfonylmethyl isocyanide (TosMIC), 1.70 g, 8.700 mmol,1.10 equiv.) was then added with stirring at −78° C. The mixture wasstirred 1 h at −78° C. 6-Chloro-5-fluoro-2-methoxynicotinaldehyde (1.50g, 7.900 mmol, 1.00 equiv) was added with stirring at −78° C. Theresulting solution was stirred 1.5 h at −78° C. Methanol was added andthe resulting solution was stirred 16 h at 80° C. The mixture wasconcentrated under vacuum. The residue was purified by silica gel withethyl acetate/petroleum ether (8:92). The collected fractions werecombined and concentrated under vacuum to yield2-(6-chloro-5-fluoro-2-methoxypyridin-3-yl)acetonitrile as yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₈H₆ClFN₂O, 201.0 [M+H], found200.8.

Step 5:2-ethyl-2-(6-(1-ethyl-5-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butanal

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, to a solution of2-(6-chloro-5-fluoro-2-methoxypyridin-3-yl)acetonitrile (400 mg, 1.900mmol, 1.00 equiv.) in DMF (30 mL), was added t-BuOK (10 mL, 9.900 mmol,5.00 equiv.) with stirring at 0° C. Iodoethane (1.50 g, 9.900 mmol, 5.00mmol) was then added and the resulting solution was stirred 16 h at 20°C. The resulting solution was quenched by H₂O, extracted with EA, andthe organic layer was concentrated under vacuum. The residue waspurified by silica gel with ethyl acetate/petroleum ether (10:90). Thecollected fractions were combined and concentrated under vacuum to yield2-(6-chloro-5-fluoro-2-methoxypyridin-3-yl)-2-ethylbutanenitrile asyellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J=8.3 Hz, 1H), 3.95 (s, 3H),2.24-2.33 (m, 2H), 1.94-2.01 (m, 2H), 0.88 (t, J=7.4 Hz, 6H).

Step 6:3-(3-(4H-1,2,4-triazol-3-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-5-fluoropyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 99 by condensation followed by demethylation to yield theproduct as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.63 (d, J=8.2 Hz, 1H), 8.16 (s, 1H), 7.83(d, J=11.2 Hz, 2H), 7.27 (d, J=11.2 Hz, 1H), 4.51-4.58 (m, 2H),2.48-2.55 (m, 2H), 2.14-2.21 (m, 2H), 1.53 (t, J=7.2 Hz, 3H), 0.79 (t,J=7.4 Hz, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −77.31, −119.68. Massspectrum (ESI, m/z): Calculated for C₂₁H₂₂F₂N₆O, 413.2 [M+H], found413.1.

Example 111 Compound #613-(2-Methyl-1-(1H-tetrazol-5-yl)propyl)-6-(naphthalen-2-yl)pyridin-2(1H)-one

Step 1:2-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-3-methylbutanenitrile

Into a 100-mL round-bottom flask, were placed2-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-3-methylbutanamide (40 mg,0.120 mmol, 1.00 equiv.), DCM (5 mL), 2,2,2-trifluoroacetic anhydride(126 mg, 0.600 mmol, 5 equiv.). The resulting solution was stirred for 5h at 15° C. The reaction progress was monitored by TLC (PE:EA=6:1). Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:6) toyield2-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-3-methylbutanenitrile as alight yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₀N₂O, 317.2 (M+H), found317.4.

Step 2:2-methoxy-3-(2-methyl-1-(1H-tetrazol-5-yl)propyl)-6-(naphthalen-2-yl)pyridine

Into a 50-mL round-bottom flask, were placed2-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-3-methylbutanenitrile (20mg, 0.063 mmol, 1.00 equiv.), toluene (5 mL), azidotrimethylsilane (36mg, 0.312 mmol, 5 equiv.), dibutylstannanone (78 mg, 0.313 mmol, 5equiv). The resulting solution was stirred for overnight at 110° C. Thereaction progress was monitored by LCMS. The reaction was then quenchedby the addition of water (10 mL). The resulting solution was extractedwith ethyl acetate (3×30 mL and the organic layers combined. Theresulting mixture was washed with brine (1×30 mL). The mixture was driedover anhydrous sodium sulfate. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:1) toyield2-methoxy-3-(2-methyl-1-(1H-tetrazol-5-yl)propyl)-6-(naphthalen-2-yl)pyridineas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₁N₅O, 360.2 (M+H), found360.2.

Step 3:3-(2-methyl-1-(1H-tetrazol-5-yl)propyl)-6-(naphthalen-2-yl)pyridin-2(1H)-one

Into a 50-mL round-bottom flask, were placed2-methoxy-3-(2-methyl-1-(1H-tetrazol-5-yl)propyl)-6-(naphthalen-2-yl)pyridine(20 mg, 0.056 mmol, 1.00 equiv.), CH₃CN (5 mL), sodium iodide (42 mg,0.280 mmol, 5 equiv.). To the mixture was then addedchlorotrimethylsilane (30 mg, 0.276 mmol, 5.00 equiv.) dropwise withstirring at 0° C. The resulting solution was stirred for 3 h at 25° C.The reaction progress was monitored by LCMS. The reaction was thenquenched by the addition of water (10 mL). The resulting solution wasextracted with ethyl acetate (3×20 mL) and the organic layers combined.The resulting mixture was washed with brine (1×20 mL). The mixture wasdried over anhydrous sodium sulfate. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The residue waspurified by by Prep-HPLC with the following conditions (1#-Waters2767-5): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, Waterof 0.05% trifluoroacetic acid and CH₃CN (20% CH₃CN up to 60% in 10 min,up to 100% in 2 min, down to 50% in 2 min; Detector, 254 nm to yield3-(2-methyl-1-(1H-tetrazol-5-yl)propyl)-6-(naphthalen-2-yl)pyridin-2(1H)-oneas a light yellow solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.22 (s, 1H), 7.90-8.01 (m, 3H), 7.84 (d,J=7.5 Hz, 1H), 7.75-7.78 (m, 1H), 7.56-7.59 (m, 2H), 6.80 (d, J=7.5 Hz,1H), 4.42 (d, J=10.2 Hz, 1H), 2.64-2.69 (m, 1H), 1.02 (d, J=6.6 Hz, 3H),0.92 (d, J=6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₀H₁₉N₅O, 346.2 (M+H), found 346.1.

Example 112 Compound #2706-(8-Fluoronaphthalen-2-yl)-3-(3-methyl-2-(1H-tetrazol-5-yl)butyl)pyridin-2(1H)-one

Step 1:2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutanenitrile

Into a 50 mL round-bottom flask were placed a solution of2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutanamide(150 mg, 0.409 mmol, 1 equiv.) in DCM (5 mL). Trifluoroacetic anhydride(4 mL) was then added. The reaction mixture was stirred for 2 h at roomtemperature. The reaction was successful and confirmed by LCMS. Themixture was concentrated under vacuum. The residue was applied onto asilica gel column with CH₂Cl₂/MeOH (5/1) to yield2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutanenitrileas light solid.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₁FN₂O, 349.2 (M+H), found349.2.

Step 2: 6-(8-fluoronaandphthalen-2-yl)-3-(3-methyl-2-(1H-tetrazol-5-yl)butyl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 111 by condensation of2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutanenitrile by azidotrimethylsilane and dibutylstannanone followed bydemethylation of6-(8-fluoronaphthalen-2-yl)-2-methoxy-3-(3-methyl-2-(1H-tetrazol-5-yl)butyl)pyridineto yield the product as a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.33 (s,1H), 8.02 (d, J=9.2 Hz, 1H),7.72-7.77 (m, 2H), 7.49-7.55 (m, 1H), 7.24-7.29 (m, 1H), 7.18 (d, J=6.8Hz, 1H), 6.54 (d, J=7.2 Hz,1H), 3.43-3.49 (m, 1H), 3.25-3.26 (m, 1H),2.84-2.90 (m, 1H), 2.11-2.17 (m, 1H), 1.08 (d, J=6.8 Hz, 3H), 0.88 (d,J=6.8 Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −124.55. Mass spectrum (ESI,m/z): Calculated for C₂₁H₂₀FN₅O, 378.2 (M+H), found 378.2.

Example 113 Compound #33-(3-(1H-tetrazol-5-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 111 by condensation followed by demethylation to yield theproduct as a white solid.

¹H NMR (300 MHz, CD₃OD) δ 8.16 (s, 1H), 7.79-7.82 (m, 2H), 7.21 (d,J=10.8 Hz, 1H), 6.84 (d, J=7.2 Hz, 1H), 4.52-4.59 (m, 2H), 2.48-2.55 (m,2H), 2.15-2.22 (m, 2H), 1.53 (t, J=7.2 Hz, 3H), 0.72-0.77 (m, 6H). ¹⁹FNMR (300 MHz, CD₃OD) 5-119.10. Mass spectrum (ESI, m/z): Calculated forC₂₀H₂₂FN₇O, 396.2 [M+H], found 396.2.

Example 114 Compound #706-(8-fluoronaphthalen-2-yl)-3-(3-methyl-1-(2H-tetrazol-5-yl)butan-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 111 by condensation followed by demethylation to yield theproduct as a yellow oil.

¹H NMR (400 MHz, CD₃OD) δ: 8.40 (s, 1H), 8.05-8.07 (m, 1H), 7.82 (d,J=8.8 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.53-7.58 (m, 1H), 7.41 (d, J=7.2Hz, 1H), 7.27-7.32 (m, 1H), 6.70 (d, J=7.2 Hz, 1H), 3.41-3.52 (m, 1H),3.32-3.38 (m, 1H), 3.13-3.19 (m, 1H), 2.21-2.28 (m, 1H), 1.15 (d, J=6.8Hz, 3H), 0.96 (d, J=6.8 Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −77.04,−124.50. Mass spectrum (ESI, m/z): Calculated ForC_(22.76)H_(20.88)F_(3.64)N₅O_(2.76), 378.2 (M−0.88CF₃COOH+H), found378.1.

Example 115 Compound #423-(3-(1,3,4-oxadiazol-2-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

Step 1:2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanoic acid

Into a 50 mL round-bottom flask were placed a solution of ethyl2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butanoate(500 mg, 1.209 mmol, 1.00 equiv.) in CH₃COOH (20 mL). HCl (10 mL) wasadded. The reaction was stirred overnight at 100° C. and monitored byLCMS. The mixture was concentrated under vacuum and extracted with ethylacetate (3×30 mL). The organic layers were combined, washed with sodiumcarbonate (aq.) and brine, dried and concentrated under vacuum to yield2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanoicacid as a yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₀H₂₂FN₃O₃, 372.2 [M+H], found372.3.

Step 2:2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanehydrazide

Into a 50 ml flask were placed a solution of2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanoicacid (200 mg, 0.538 mmol, 1.00 equiv.) in DCM/DMF (5 mL/3 mL), and HATU(409 mg, 1.077 mmol, 2.00 equiv.), EDCl (206 mg, 1.077 mmol, 2.00equiv.), DIPEA (139 mg, 1.077 mmol, 2.00 equiv.) were added. The mixturewas stirred for 30 min, and NH₂NH₂H₂O (135 mg, 2.692 mmol, 5.00 equiv.)was added. The mixture was stirred overnight at room temperature. Themixture was extracted with ethyl acetate (3×30 mL). The organic layerswere combined, washed with sodium carbonate (aq.) and brine, dried andconcentrated under vacuum to yield2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanehydrazideas a yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₀H₂₄FN₅O₂, 386.2 [M+H], found386.2.

Step 3:3-(3-(1,3,4-oxadiazol-2-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

Into a 50 ml round-bottom flask were placed a solution of2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanehydrazide(50 mg, 0.130 mmol, 1.00 equiv.) in EtOH (5 ml).

Triethoxymethane (96 mg, 0.648 mmol, 5.00 equiv.), NH₄Cl (35 mg, 0.654mmol, 5.00 equiv.) was added. The mixture was stirred overnight at 80°C. The reaction was monitored by LCMS. The reaction was concentratedunder vacuum. The residue was dissolved in DMF. The solution waspurified by Prep-HPLC with the following conditions: Column, SunFirePrep C18, 5 um, 19*100 mm; mobile phase, Water of 0.05% NH₄HCO₃ andCH₃CN (28% CH₃CN up to 50% in 10 min, up to 100% in 2 min, down to 28%in 2 min; Detector, 220 nm, 254 nm to yield3-(3-(1,3,4-oxadiazol-2-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-oneas a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.83 (s, 1H), 8.16 (s, 1H), 7.74-7.82 (m,2H), 7.19-7.23 (m, 1H), 6.83 (d, J=7.5 Hz, 1H), 4.52-4.60 (m, 2H),2.38-2.55 (m, 2H), 2.10-2.25 (m, 2H), 1.50-1.60 (m, 3H), 0.75-0.85 (m,6H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −119.085. Mass spectrum (ESI, m/z):Calculated for C₂₁H₂₂FN₅O₂, 396.2 [M+H], found 396.2.

Example 116 Compound #386-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(5-isopropyl-1,3,4-oxadiazol-2-yl)pentan-3-yl)pyridin-2(1H)-one

Into an 8 ml tube were placed a solution of 2-methylpropanethioamide (12mg, 0.116 mmol, 1.50 equiv.) in CH₃CN (5 mL). Iodomethane (22 mg, 0.155mmol, 2.00 equiv.) was added. The reaction was stirred for 1.5 h at 50°C.

The mixture was concentrated under vacuum. The residue was dissolved inDMF (5 mL), and2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanehydrazidewas added. The reaction was stirred overnight at 140° C. The reactionwas monitored by LCMS. The mixture was extracted with ethyl acetate(3×20 mL). The organic layers were combined, washed with sodiumcarbonate (aq.) and brine, dried and concentrated under vacuum. Theresidue was dissolved in DMF (2 mL). The solution was purified byPrep-HPLC with the following conditions: Column, SunFire Prep C18, 5 um,19*100 mm; mobile phase, Water of 0.05% NH₄HCO₃ and CH₃CN (35% CH₃CN upto 40% in 10 min, up to 100% in 2 min, down to 30% in 2 min; Detector,220 nm, 254 nm to yield6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(5-isopropyl-1,3,4-oxadiazol-2-yl)pentan-3-yl)pyridin-2(1H)-oneas a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.13 (s, 1H), 7.80 (s, 1H), 7.71 (d, J=7.6Hz, 1H), 7.15-7.22 (m, 1 H), 6.80 (d, J=7.2 Hz, 1H), 4.48-4.58 (m, 2H),3.10-3.20 (m, 1H), 2.30-2.45 (m, 2H), 2.05-2.15 (m, 2H), 1.48-1.53 (m,3H), 1.35 (s, 6H), 0.72-0.80 (m, 6H). ¹⁹F NMR (400 MHz, CD₃OD) δ:−119.1.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₈FN₅O₂, 438.2 [M+H], found438.2.

Example 117 Compound #2716-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(5-methyl-1,3,4-oxadiazol-2-yl)pentan-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 115 by condensation followed by demethylation to yield theproduct as white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.15 (s, 1H), 7.81 (s, 1H), 7.73 (d, J=7.5Hz, 1H), 7.18-7.22 (m, 1 H), 6.81 (d, J=7.2 Hz, 1H), 4.45-4.60 (m, 2H),2.49 (s, 3H), 2.30-2.45 (m, 2H), 2.01-2.15 (m, 2H), 1.45-1.55 (m, 3H),0.71-0.80 (m, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −119.1. Mass spectrum(ESI, m/z): Calculated for C₂₂H₂₄FN₅O₂: 410.2 [M−NH₂], found: 410.2.

Example 118 Compound #456-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pentan-3-yl)py-ridine-2(1H)-one

Into a 25 ml flask were placed a solution of2,2,2-trifluoroethanethioamide (50 mg, 0.388 mmol, 1.50 equiv.) in DCM(10 mL). Methyl trifluoromethanesulfonate (85 mg, 0.517 mmol, 2.00equiv.) was added. The reaction was stirred for 3 h at 25° C. Themixture was concentrated under vacuum. The residue was dissolved in DMF(5 mL), and2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanehydrazide(100 mg, 0.259 mmol, 1.00 equiv.) was added. The reaction was stirredfor 2 h at 140° C. The reaction was monitored by LCMS. The mixture wasconcentrated under vacuum. The residue was dissolved in DMF (2 mL). Thesolution was purified by Prep-HPLC with the following conditions:Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, Water of 0.05%NH₄HCO₃ and CH₃CN (35% CH₃CN up to 60% in 10 min, up to 100% in 2 min,down to 35% in 2 min; Detector, 220 nm, 254 nm to yield6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pentan-3-yl)pyridin-2(1H)-oneas a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ: 12.08 (s, 1H), 8.23 (s, 1H), 8.07 (s, 1H),7.69 (d, J=7.5 Hz, 1H), 7.37 (d, J=11.4 Hz, 1H), 6.80-6.90 (m, 1H),4.40-4.60 (m, 2H), 2.18-2.35 (m, 2H), 2.00-2.13 (m, 2H), 1.35-1.45 (m,3H), 0.65-0.80 (m, 6H). ¹⁹F NMR (300 MHz, DMSO-d₆) δ: −64.365, −117.608.Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₁F₄N₅O₂, 464.2 [M+H],found 464.1.

Example 119 Compound #483-(3-(5-(dimethylamino)-1,3,4-thiadiazol-2-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

Step 1:(E)-2-(2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butylidene)-N,N-dimethylhydrazinecarbothioamide

Into a 100-mL round-bottom flask, were placed2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butanal(80 mg, 0.217 mmol, 1.00 equiv.), N,N-dimethylhydrazinecarbothioamide(39 mg, 0.325 mmol, 1.00 equiv.), MeOH (5 mL), AcOH (0.5 mL), H₂O (0.5mL). The reaction was stirred overnight at 50° C. The reaction progresswas monitored by TLC (PE:EA=1:1). The resulting solution concentrated.The residue was purified by silica gel chromatography (0-50%EtOAc/petroleum ether) to yield(E)-2-(2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butylidene)-N,N-dimethylhydrazinecarbothioamideas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₃₁FN₆OS, 471.2 [M+H],found. 471.2.

Step 2:5-(3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)pentan-3-yl)-N,N-dimethyl-1,3,4-thiadiazol-2-amine

Into a 100-mL round-bottom flask were placed(E)-2-(2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butylidene)-N,N-dimethylhydrazinecarbothioamide(80 mg, 0.170 mmol, 1.00 equiv.), I₂ (65 mg, 0.255 mmol, 1.50 equiv.),K₂CO₃ (70 mg, 0.510 mmol, 3.00 equiv.), 1,4-dioxane (8 mL). The reactionwas purged with an inert atmosphere of nitrogen and was stirred 4 h at90° C. The reaction progress was monitored by TLC (DCM;MeOH=10:1). Theresulting solution concentrated. The residue was purified by silica gelchromatography (0-20% DCM/MeOH) to yield5-(3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)pentan-3-yl)-N,N-dimethyl-1,3,4-thiadiazol-2-amineas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₉FN₆OS, 469.2 [M+H],found. 469.1.

Step 3:3-(3-(5-(dimethylamino)-1,3,4-thiadiazol-2-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation with TMSCl/NaI to yield the productas an off-white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.14 (s, 1H), 7.80 (s, 1H), 7.73 (d, J=7.5Hz, 1H), 7.20 (d, J=11.1 Hz, 1H), 6.78 (d, J=7.2 Hz, 1H), 4.51-4.58 (m,2H), 3.10 (s, 6H), 2.50-2.57 (m, 2H), 2.05-2.15 (m, 2H), 1.50-1.55 (m,3H), 0.78-0.83 (m, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −119.14. Massspectrum (ESI, m/z): Calculated for C₂₃H₂₇FN₆OS, 455.2 [M+H], found455.3.

Example 120 Compound #523-(3-(5-amino-1,3,4-thiadiazol-2-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 119 by condensation followed by demethylation to yield theproduct as a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.14 (s, 1H), 7.78-7.80 (m, 2H), 7.17-7.20 (m1H), 6.81 (d, J=6.6 Hz, 1H), 4.51-4.56 (m, 2H), 2.44-2.53 (m, 2H),2.00-2.09 (m, 2H), 1.50-1.53 (m, 3H), 0.80-0.84 (m, 6H). ¹⁹F NMR (400MHz, CD₃OD) δ: −77.16, −118.93. Mass spectrum (ESI, m/z): Calculated forC_(22.04)H_(23.52)F_(2.56)N₆O_(2.04)S, 427.2 [M−0.52CF₃COOH+H], found427.3.

Example 121 Compound #573-(3-(5-(dimethylamino)-1,3,4-oxadiazol-2-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

Step 1: N,N-dimethylhydrazinecarboxamide

Into a 100-mL round-bottom flask, to a stirred solution of hydrazinehydrate (441 mg, 8.809 mmol, 1.00 equiv.) in EtOH (20 mL) was added asolution of dimethylcarbamyl chloride (947 mg, 8.809 mmol, 1.00 equiv.)in Et₂O (10 mL) dropwise over 18 min in an ice-bath. The resultingsolution was stirred in the ice-bath for 1 h. The precipitate wasremoved by vacuum filtration and the filtrated was concentrated to yielda white solid.

Step 2:(E)-2-(2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butylidene)-N,N-dimethylhydrazinecarboxamide

Into a 100-mL round-bottom flask, were placed2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butanal(80 mg, 0.217 mmol, 1.00 equiv.), N,N-dimethylhydrazinecarboxamide (33mg, 0.325 mmol, 1.00 equiv.), MeOH (5 mL), AcOH (0.5 mL), H₂O (0.5 mL).The reaction was stirred overnight at 50° C. The reaction progress wasmonitored by TLC (PE:EA=1:1). The resulting solution concentrated. Theresidue obtained was purified by silica gel chromatography (0-50%EtOAc/petroleum ether) to yield(E)-2-(2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butylidene)-N,N-dimethylhydrazinecarboxamide as a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₃₁FN₆O₂, 455.2 [M+H], found0.455.4.

Step 3:5-(3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)pentan-3-yl)-N,N-dimethyl-1,3,4-oxadiazol-2-amine

Into a 100-mL round-bottom flask were placed(E)-2-(2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butylidene)-N,N-dimethylhydrazinecarboxamide(50 mg, 0.110 mmol, 1.00 equiv.), I₂ (42 mg, 0.165 mmol, 1.50 equiv.),K₂CO₃ (46 mg, 0.330 mmol, 3.00 equiv.), 1,4-dioxane (8 mL). The reactionwas purged with an inert atmosphere of nitrogen and was stirred 4 h at90° C. The reaction progress was monitored by TLC (DCM;MeOH=10:1). Theresulting solution concentrated. The residue obtained was purified bysilica gel chromatography (0-20% DCM/MeOH) to yield5-(3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)pentan-3-yl)-N,N-dimethyl-1,3,4-oxadiazol-2-amineas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₉FN₆O₂, 453.2 [M+H], found453.1.

Step 4:3-(3-(5-(dimethylamino)-1,3,4-oxadiazol-2-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation with TMSCl/NaI to yield the productas a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.10 (s, 1H), 7.78 (s, 1H), 7.64 (d, J=7.5Hz, 1H), 7.16 (d, J=10.8 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 4.47-4.55 (m,2H), 2.98 (s, 6H), 2.27-2.37 (m, 2H), 2.00-2.12 (m, 2H), 1.46-1.51 (m,3H), 0.74-0.79 (m, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −119.11. Massspectrum (ESI, m/z): Calculated for C₂₃H₂₇FN₆O₂, 439.2 [M+H], found439.1.

Example 122 Compound #513-(3-(5-amino-1,3,4-oxadiazol-2-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

Into a 50-mL round-bottom flask, were placed2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-hydroxypyridin-3-yl)butanehydrazide(100 mg, 0.259 mmol, 1.00 equiv.), methyl carbamimidothioate (47 mg,0.519 mmol, 2.00 equiv.), pyridine (5 mL). The reaction was stirred 2 hat 120° C. The reaction progress was monitored by LCMS. The resultingsolution concentrated. The residue obtained was purified by silica gelchromatography (0-20% DCM/MeOH) yield residue. The residue was purifiedby Prep-HPLC with the following conditions (1#-Waters 2767-5): Column,SunFire Prep C18, 5 um, 19*100 mm; mobile phase, Water of 0.05% NH₄HCO₃and CH₃CN (20% CH₃CN up to 50% in 10 min, up to 100% in 2 min, down to20% in 2 min; Detector, 254 nm to yield3-(3-(5-amino-1,3,4-oxadiazol-2-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-oneas a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.11 (s, 2H), 7.84-7.90 (m, 2H), 7.55 (d,J=12.0 Hz, 1H), 4.53-4.59 (m, 2H), 1.98-2.07 (m, 4H), 1.51-1.55 (m, 3H),1.07-1.12 (m, 6H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −120.12. Mass spectrum(ESI, m/z): Calculated for C₂₁H₂₃FN₆O₂, 411.2 [M+H], found. 411.2.

Example 123 Compound #533-(3-(5-ethyl-1,3,4-oxadiazol-2-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 121 by condensation followed by demethylation with TMSCl/NaIto yield the product as a light yellow solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.10 (s, 1H), 7.77 (s, 1H), 7.69 (d, J=7.5Hz, 1H), 7.14-7.18 (m, 1 H), 6.77 (d, J=7.5 Hz, 1H), 4.45-4.55 (m, 2H),2.75-2.85 (m, 2H), 2.28-2.43 (m, 2H), 2.03-2.15 (m, 2H), 1.45-1.52 (m,3H), 1.25-1.31 (m, 3H), 0.68-0.80 (m, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ:−119.084. Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₆FN₅O₂,424.2[M+H], found 424.2.

Example 124 Compound #306-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(oxazol-2-yl)pentan-3-yl)pyridin-2(1H)-one

Into a 50-mL round-bottom flask, were placed2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butanamide(15 mg, 0.039 mmol, 1.00 equiv.), vinylene carbonate (4 mg, 0.043 mmol,1.10 equiv.), PPA (2 mL). The resulting solution was stirred 3.0 h at165° C. The reaction was then quenched by the addition of H₂O, extractedwith EA, the organic layers was concentrated under vacuum, then purifiedby Prep-HPLC with the following conditions (16#-Waters 2767-5): Column,SunFire Prep C18,19*100 mm, 5 um; mobile phase, Water with 0.05% NH₄HCO₃and CH₃CN (20% CH₃CN up to 42% in 10 min, up to 100% in 0.1 min);Detector, UV 220 & 254 nm to yield6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(oxazol-2-yl)pentan-3-yl)pyridin-2(1H)-oneas a white solid.

¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 7.77 (d, J=10.8 Hz, 2H), 7.67(d, J=7.6 Hz, 1H), 7.18 (d, J=10.8 Hz, 1H), 7.07 (s, 1H), 6.77 (d, J=7.6Hz, 1H), 4.50-4.55 (m, 2H), 2.36-2.45 (m, 2H), 2.09-2.19 (m, 2H),1.49-1.52 (m, 3H), 0.70-0.74 (m, 6H). ¹⁹F NMR (400 MHz, CD₃OD) δ−119.17.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₃FN₄O₂, 395.2 [M+H], found395.3.

Example 125 Compound #416-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(oxazol-2-ylmethyl)pentan-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 124 by condensation followed by demethylation to yield theproduct as as white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.15 (s, 1H), 7.83 (s, 1H), 7.71 (s, 1H),7.39 (d, J=7.5 Hz, 1H), 7.19-7.23 (m, 1H), 7.00 (s, 1H), 6.68 (d, J=7.5Hz, 1H), 4.56-4.58 (m, 2H), 3.55 (s, 2H), 2.00-2.15 (m, 2H), 1.85-1.95(m, 2H), 1.53-157 (m, 3H), 0.84-0.89 (m, 6H). ¹⁹F NMR (300 MHz, CD₃OD)δ: 119.23.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₅FN₄O₂, 409.2 [M+H],found. 409.0.

Example 126 Compound #296-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(isoxazol-3-yl)pentan-3-yl)pyridin-2(1H)-one

Step 1:4-ethyl-4-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)hex-1-yn-3-ol

Into a 50 ml round-bottom flask were placed a solution of2-ethyl-2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)butanal(500 mg, 1.353 mmol, 1.00 equiv.) in THF (20 mL), the mixture was cooledto −78° C. under nitrogen atmosphere. Ethynylmagnesium bromide (5.42 mL,2.710 mmol, 2.00 equiv.) was added dropwise. The reaction was stirredovernight and monitored by LCMS. The mixture was quenched with water andextracted with ethyl acetate (3×30 mL). The organic layers werecombined, washed with sodium carbonate (aq.) and brine, dried andconcentrated under vacuum. The residue was purified by silica gel columndeveloped with PE/EA (6/1) to yield4-ethyl-4-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)hex-1-yn-3-olas a light yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₆FN₃O₂: 396.2[M+H], found:396.4.

Step 2:4-ethyl-4-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)hex-1-yn-3-one

To a solution of4-ethyl-4-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)hex-1-yn-3-olin DCM at 0° C. was added Dess-Martin periodinane in several portions.The mixture was stirred for 2 h at 25° C. The reaction was monitored byLCMS. The mixture was quenched by NaHCO₃/Na₂S₂O₃ and concentrated undervacuum to applied on flash column chromatography silica gel (PE/EA=3/1)to yield4-ethyl-4-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)hex-1-yn-3-oneas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for for C₂₃H₂₄FN₃O₂: 394.2[M+H],found: 394.1.

Step 3:3-(3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)pentan-3-yl)isoxazole

To a solution of4-ethyl-4-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)hex-1-yn-3-ol(90 mg, 0.229 mmol, 1.00 equiv.) in EtOH (10 mL) was added NH₂OH.HCl (37mg, 0.530 mmol, 2.00 equiv.), Na₂CO₃ (48 mg, 0.457 mmol, 2.00 equiv.).The mixture was stirred at 80° C. overnight. The reaction was monitoredby LCMS. The mixture was concentrated under vacuum. The residue wasdistilled in toluene (10 mL). TsOH (118 mg, 0.686 mmol, 3.00 equiv.), 4Å molecular sieves (100 mg) were added. The mixture was stirredovernight at 100° C. The reaction was monitored by LCMS. The mixture wasconcentrated under vacuum and purified by thin layer chromatographydeveloped with PE/EA (6/1) to yield3-(3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)pentan-3-yl)isoxazoleas a yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₅FN₄O₂: 409.2[M+H], found.409.4.

Step 4:6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-(isoxazol-3-yl)pentan-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation with TMSCl/NaI yield the product aswhite solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.29 (d, J=2.0 Hz, 1H), 8.15 (s, 1H), 7.81(s, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.18-7.25 (m, 1H), 6.79 (d, J=7.6 Hz,1H), 6.25 (d, J=2.0 Hz, 1H), 4.48-4.60 (m, 2H), 2.38-2.50 (m, 2H),2.00-2.15 (m, 2H), 1.50-1.58 (m, 3H), 0.70-0.80 (m, 6H). ¹⁹F NMR (400MHz, CD₃OD) δ: −119.18. Mass spectrum (ESI, m/z): Calculated forC₂₂H₂₃FN₄O₂: 395.2[M+H], found: 395.1.

Example 127 Compound #376-(1-ethyl-4-fluoro-1H-indazol-6-yl)-5-fluoro-3-(3-(oxazol-2-yl)pentan-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 126 by condensation followed by demethylation to yield theproduct as white solid.

¹H NMR (300 MHz, CD₃OD) δ 8.15 (s, 1H), 7.81-7.86 (m, 2H), 7.70 (d,J=11.3 Hz, 1H), 7.29 (d, J=11.2 Hz, 1H), 7.13 (s, 1H), 4.51-4.55 (m,2H), 2.42-2.49 (m, 2H), 2.16-2.23 (m, 2H), 1.52 (t, J=7.2 Hz, 3H), 0.76(t, J=7.4 Hz, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ −77.38, −119.91. Massspectrum (ESI, m/z): Calculated for C₂₂H₂₂F₂N₄O₂, 413.2 [M+H], found413.1.

Example 128 Compound #953-(1-(6-(8-Fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)-1,2,4-oxadiazol-5(4H)-one

Step 1:2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanenitrile

Into a 100-mL 3-neck-flask purged and maintained with an inert atom ofnitrogen, were placed(Z)-5-(2-(6-chloro-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione(1.1 g, 3.3 mmol, 1 equiv.), 2-hydroxy-2-methylpropanenitrile (575 mg,6.7 mmol, 2 equiv.), PPh₃ (2.6 g, 10 mmol, 3 equiv.), THF (30 mL). DIAD(2.0 g, 10 mmol, 3 equiv.) was then added with stirring at 0° C. Theresulting solution was stirred 16 h at 20° C. The mixture wasconcentrated under vacuum. The residue was purified by silica cal columnwith ethyl acetate/petroleum ether (6:94) to yield(Z)-5-(2-(6-chloro-2-methoxypyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dioneas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₁₉FN₂O, 335.1 (M+H), found335.1.

Step 2:(Z)-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-N′-hydroxy-3-methylbutanimidamide

Into a 100-mL sealed tube, were placed3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentanenitrile(600 mg, 1.8 mmol, 1 equiv.), EtOH (30 ml), NH₂OH.HCl (1.2 g, 17 mmol,10 equiv.), EtONa (1.5 g, 22 mmol, 12 equiv.). The solution was stirredat 90° C. overnight. The reaction progress was monitored by TLC/LCMS.The mixture was concentrated under vacuum.

The residue was purified by silica cal column with DCM/MeOH (96:4) toyield3-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-1,2,4-oxadiazol-5(4H)-oneas a yellow oil.

Mass spectrum (ESI, m/z): Calculated For C₂₁H₂₂FN₃O₂, 368.2 (M+H), found368.1.

Step 3:3-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-1,2,4-oxadiazol-5(4H)-one

Into a 50-mL sealed tube, were placed(Z)-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-N′-hydroxy-3-methylbutanimidamide(500 mg, 1.4 mmol, 1 equiv.), THF (20 mL), DBU (310 mg, 2.0 mmol, 1.5equiv.), CDI (330 mg, 2.0 mmol, 1.5 equiv.). The solution was stirred at70° C. overnight. The mixture was concentrated under vacuum. The residuewas purified by silica gel column with DCM/MeOH (96:4) to yield3-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-1,2,4-oxadiazol-5(4H)-oneas a yellow oil.

Mass spectrum (ESI, m/z): Calculated For C₂₂H₂₀FN₃O₃, 394.1 (M+H), found394.1.

Step 4:3-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)-1,2,4-oxadiazol-5(4H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation of3-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-1,2,4-oxadiazol-5(4H)-onewith TMSCl/NaI in CH₃CN to yield the product as a white solid.

¹H NMR (300 MHz, CD₃OD, ppm) δ: 8.42 (s, 1H), 8.08 (d, J=7.2 Hz, 1H),7.83-7.88 (m, 1H), 7.72-7.79 (m, 2H), 7.54-7.59 (m, 1H), 7.27-7.33 (m,1H), 6.83 (d, J=7.5 Hz, 1H), 3.92 (d, J=9.9 Hz, 1H), 2.51-2.57 (m, 1H),1.09 (d, J=6.6 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD,ppm) δ: −124.39. Mass spectrum (ESI, m/z): Calculated For C₂₁H₁₈FN₃O₃,380.1 (M+H), found 380.2.

Example 129 Compound #723-(2-(6-(8-Fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)-1,2,4-oxadiazol-5(4H)-one

The title compound was prepared according to the procedure as describedin Example 128 by reacting3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-methylpentanenitrilewith NH₂OH.HCl and then cyclization of(Z)-3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-N′-hydroxy-4-methylpentanimidamideby CDI/DBU followed by demethylation of3-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)-1,2,4-oxadiazol-5(4H)-onewith TMSCl/NaI in CH₃CN to yield the product as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ: 12.22 (s, 1H), 11.99 (brs, 1H), 8.46 (s,1H), 8.07 (d, J=8.8 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.4 Hz,1H), 7.52-7.57 (m, 1H), 7.35-7.40 (m, 2H), 6.79 (brs, 1H), 3.02-3.06 (m,1H), 2.89-2.91 (m, 2H), 2.05-2.10 (m, 1H). 0.94 (d, J=6.8 Hz, 3H), 0.81(d, J=6.8 Hz, 3H). ¹⁹F NMR (400 MHz, DMSO-d₆) δ: −75.00, −123.71. Massspectrum (ESI, m/z): Calculated for C₂₂H₂₀FN₃O₃−0.98TFA, 394.2 (M+H),found 394.1.

Example 130 Compound #2723-(1-(5-chloro-6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutan-2-yl)-1,2,4-oxadiazol-5(4H)-one

The title compound was prepared according to the procedure as describedin Example 128 by cyclization followed by demethylation to yield theproduct as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.23 (s, 1 H), 7.72 (d, J=6.3 Hz, 1 H),7.68-7.73 (m, 3 H), 7.31-7.45 (m, 1 H), 6.58 (d, J=9.6 Hz, 1 H),3.29-3.31 (m, 1 H), 3.01-3.18 (m, 1 H), 2.72-2.85 (m, 1 H), 1.94-2.13(m, 1 H), 1.18 (d, J=6.6 Hz, 3 H), 1.02 (d, J=6.9 Hz, 3 H). ¹⁹F NMR (300MHz, CD₃OD) δ: −77.14, −129.37. Mass spectrum (ESI, m/z): Calculated forC_(23.68)H_(19.84)ClF_(3.52)N₃O_(4.68), 428.1 (M−0.84CF₃COOH+H), found428.0.

Example 131 Compound #2773-(1-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)-1,2,4-oxadiazol-5(4H)-one

The title compound was prepared according to the procedure as describedin Example 128 by cyclization followed by demethylation to yield theproduct as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.16 (s, 1 H), 7.83 (s, 1 H), 7.73 (d, J=7.5Hz, 1 H), 7.22 (d, J=11.7 Hz, 1 H), 6.81 (d, J=7.2 Hz, 1 H), 4.52-4.60(m, 2 H), 3.92 (d, J=9.9 Hz, 1 H), 2.51-2.55 (m, 2 H), 1.51-1.56 (t,J=7.2 Hz, 3 H), 1.10 (d, J=6.6 Hz, 3 H), 0.98 (d, J=6.6 Hz, 3 H). ¹⁹FNMR (300 MHz, CD₃OD) δ: −119.03. Mass spectrum (ESI, m/z): Calculatedfor C₂₀H₂₀FN₅O₃, 398.2 [M+H], found 398.0.

Example 132 Compound #2783-(1-(6-(4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)-1,2,4-oxadiazol-5(4H)-one

The title compound was prepared according to the procedure as describedin Example 128 by cyclization followed by demethylation to yield theproduct as a yellow solid.

¹H NMR (300 MHz, CD₃OD) δ: 7.69 (d, J=7.2 Hz, 1H), 6.99 (s, 1H), 6.88(d, J=6.6 Hz, 1 H), 6.81 (d, J=9.0 Hz, 1H), 6.59 (d, J=7.5 Hz, 1H),4.25-4.28 (m, 2H), 3.85-3.88 (m, 1H), 3.44-3.51 (m, 2 H), 3.32-3.38 (m,3H), 2.43-2.51 (m, 1H), 1.20-1.22 (t, J=6.9 Hz, 3H), 1.07 (d, J=6.6 Hz,3H), 0.95 (d, J=6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₁H₂₄N₄O₄, 397.2 [M+H], found 397.0.

Example 133 Compound #43-(3-(4H-1,2,4-triazol-3-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one-one

Step 1: 2-(6-chloro-2-methoxypyridin-3-yl)-2-ethylbutanenitrile

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, to a solution of2-(6-chloro-2-methoxypyridin-3-yl)acetonitrile (300 mg, 1.640 mmol, 1.00equiv.) in DMF (10 mL), was added t-BuOK (4.9 mL, 4.900 mmol, 3.00equiv.) with stirring at 0° C. Iodoethane (769 mg, 4.900 mmol) was thenadded and the resulting solution was stirred 16 h at 20° C. The mixturewas quenched by the addition of H₂O, extracted with EA, the organiclayers was concentrated under vacuum. The residue was purified bychromatogram on silica gel with ethyl acetate/petroleum ether (2:98) toyield 2-(6-chloro-2-methoxypyridin-3-yl)-2-ethylbutanenitrile as ayellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₂H₁₅ClN₂O, 239.1 [M+H], found238.9.

Step 2:3-(3-(4H-1,2,4-triazol-3-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one-one

Into a 50-mL round-bottom flask, were placed3-(3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)pentan-3-yl)-1,2,4-oxadiazol-5(4H)-one(30 mg, 0.070 mmol, 1.00 equiv.), NaI (31 mg, 0.210 mmol, 3.00 equiv.),TMSCl (22 mg, 0.210 mmol, 3.00 equiv.), CH₃CN (5 mL). The resultingsolution was stirred overnight at 30° C. The reaction was then quenchedby the addition of MeOH. The resulting mixture was concentrated undervacuum.

Na₂S₂O₃ (aq) was added and the resulting residue purified by Prep-HPLCwith the following conditions (16#-Waters 2767-5): Column, SunFire PrepC18,19*100 mm, 5 um; mobile phase, Water with 0.05% TFA and CH₃CN (15%CH₃CN up to 60% in 10 min, up to 100% in 0.1 min); Detector, UV 220 &254 nm to yield3-(3-(4H-1,2,4-triazol-3-yl)pentan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-oneas a white solid.

¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 7.80 (s, 1H), 7.65 (d, J=9.2 Hz,1H), 7.18 (d, J=10.8 Hz, 1H), 6.78 (d, J=7.2 Hz, 1H), 4.56 (t, J=8.8 Hz,2H), 2.21-2.27 (m, 2H), 1.92-1.99 (m, 2H), 1.51 (t, J=6.4 Hz, 3H),0.79-0.83 (m, 6H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −78.00, −132.94. Massspectrum (ESI, m/z): Calculated for C₂₁H₂₂FN₅O₃, 412.2 [M+H], found412.2.

Example 134 Compound #993-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)-1,2,4-oxadiazol-5(4H)-one

Step 1: (Z)-ethyl 3-(6-chloro-2-methoxypyridin-3-yl)-4-methylpent-2-enoate

To a solution of ethyl 2-(trimethylsilyl)acetate (3.65 g, 22.753 mmol,2.00 equiv.) in dry THF (70 mL) was added lithiumbis(trimethylsilyl)amide (22.75 ml, 22.753 mmol, 2.00 equiv.) at −78° C.under nitrogen atmosphere into a 250-mL round-bottom flask (the flaskwas evacuated and flushed three times with nitrogen) and the reactionmixture was stirred at this temperature for 45 min.1-(6-Chloro-2-methoxypyridin-3-yl)-2-methylpropan-1-one (2.43 g, 11.377mmol, 1.00 equiv.) in dry THF (30 mL) was added into the solution andthe reaction was stirred for another 45 min. The reaction progress wasmonitored by LCMS. A saturated solution of NH₄Cl was added to thereaction mixture. The resulting solution was extracted with ethylacetate. The organic layers were combined, washed with Na₂SO₄ (aq.) andbrine, dried and concentrated under vacuum. The residue was applied on asilica gel column and eluted with EA/PE(5/95) to yield (Z)-ethyl3-(6-chloro-2-methoxypyridin-3-yl)-4-methylpent-2-enoate as a yellowoil.

Mass spectrum (ESI, m/z): Calculated for C₁₄H₁₈ClNO₃, 284.1 [M+H], found284.0.

Step 2:5-(2-(6-(7-chloro-1-methyl-1H-benzo[d]imidazol-5-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dione

Into a 100-mL round-bottom flask, were placed (Z)-ethyl3-(6-chloro-2-methoxypyridin-3-yl)-4-methylpent-2-enoate (2.10 g, 7.410mmol, 1.00 equiv.) and platinumoxide hydrate (544.18 mg, 2.220 mmol,0.30 equiv.) in MeOH (12 mL). To the mixture was then introduced H₂. Theresulting solution was stirred for 2.0 h at 25° C. The resultingsolution was stirred for 3.0 h at 25° C. The reaction was monitored byLCMS. The solids were filtered out. The resulting solution was extractedwith ethyl acetate. The organic layers were combined, washed with Na₂SO₄(aq.) and brine, dried and concentrated under vacuum. The residue wasapplied on a silica gel column and eluted with EA:PE (3:1) to yield5-(2-(6-(7-chloro-1-methyl-1H-benzo[d]imidazol-5-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)oxazolidine-2,4-dioneas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₄H₂₀ClNO₃, 286.1 [M+H], found286.1.

Step 3: 3-(6-chloro-2-methoxypyridin-3-yl)-4-methylpentanoic acid

Into a 100-mL round-bottom flask, were placed a solution of ethyl3-(6-chloro-2-methoxypyridin-3-yl)-4-methylpentanoate (1.90 g, 6.649mmol, 1.00 equiv.) and potassium hydroxide (3.80 g, 67.729 mmol, 10.00equiv.) in EtOH (4 mL), THF (8 mL), H₂O (8 mL). The resulting solutionwas stirred overnight at 90° C. The reaction was monitored by LCMS. Theresulting solution was extracted with Et₂O, and water layers wereadjusted to pH 5˜6 with 2 N HCl, then extracted with ethyl acetate. Theorganic layers were combined and concentrated under vacuum. The residuewas applied on a silica gel column and eluted with EA/PE (1/1) to yield3-(6-chloro-2-methoxypyridin-3-yl)-4-methylpentanoic acid as a yellowoil.

Mass spectrum (ESI, m/z): Calculated for C₁₂H₁₆ClNO₃, 258.1 [M+H], found258.1.

Step 4: 3-(6-chloro-2-methoxypyridin-3-yl)-4-methylpentanamide

Into a 50-ml round-bottom flask, were placed a solution of3-(6-chloro-2-methoxypyridin-3-yl)-4-methylpentanoic acid (20 mg, 0.078mmol, 1.00 equiv.). Ammoniumchloride (7.30 mg, 0.136 mmol, 2.00 equiv.),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophospate (53 mg, 0.139 mmol, 2.00 equiv.) in DCM (3 mL) andDMF (3 mL), and then DIPEA (18 mg, 0.139 mmol, 2.00 equiv.) were added.The resulting solution was stirred overnight at 25° C. The reaction wasmonitored by LCMS. The resulting solution was eluted with H₂O, extractedwith DCM. The organic layers were combined, washed with brine, dried andconcentrated under vacuum. The residue was applied on a silica gelcolumn and eluted with EA/PE (2/1) to yield3-(6-chloro-2-methoxypyridin-3-yl)-4-methylpentanamide as yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₂H₁₇ClN₂O₂, 257.1 [M+H],found 257.1.

Step 5: 3-(6-chloro-2-methoxypyridin-3-yl)-4-methylpentanenitrile

Into a 50-ml round-bottom flask, were placed a solution of3-(6-chloro-2-methoxypyridin-3-yl)-4-methylpentanamide (650 mg, 2.532mmol, 1.00 equiv.) in DCM (7.5 mL), then TFAA (1.5 mL) was added. Theresulting solution was stirred for 2.0 h at 25° C. The reaction wasmonitored by LCMS. The resulting solution was eluted with H₂O, extractedwith DCM. The organic layers were combined, washed with brine, dried andconcentrated under vacuum. The residue was applied on a silica gelcolumn and eluted with PE:EA=1:1 to yield3-(6-chloro-2-methoxypyridin-3-yl)-4-methylpentanenitrile as a yellowoil.

Mass spectrum (ESI, m/z): Calculated for C₁₂H₁₅ClN₂O, 239.1 [M+H], found239.0.

Step 6:3-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutyl)-1,2,4-oxadiazol-5(4H)-one

The title compound was prepared according to the procedure as describedin Example 128 by cyclization followed by demethylation to yield theproduct as a yellow solid yellow solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.13 (s, 1H), 7.79 (s, 1H), 7.42 (d, J=7.2Hz, 1 H), 7.19 (d, J=10.8 Hz, 1H), 6.68 (d, J=7.2 Hz, 1H), 4.52-4.62 (m,2H), 3.10-3.15 (m, 1H), 2.82-2.95 (m, 2H), 2.22-2.27 (m, 1 H), 1.52 (t,J=7.2 Hz, 3H), 1.05 (d, J=7.2 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H). ¹⁹F NMR(400 MHz, CD₃OD) δ: −76.94, −119.33. Mass spectrum (ESI, m/z):Calculated For C₂₁H₂₂FN₅O₃, 412.2 [M+H], found 412.3.

Example 135 Compound #159 and #160 and #1613-(1-(4H-1,2,4-triazol-3-ylamino)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-oneand3-(1-(3-amino-4H-1,2,4-triazol-4-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-oneand3-(1-(3-amino-1H-1,2,4-triazol-1-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

Step 1:1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-ol

Into a 50-mL round-bottom flask, were placed1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-one(200 mg, 0.619 mmol, 1 equiv.), MeOH (8 mL), NaBH₄ (47 mg, 1.242 mmol, 2equiv.). The resulting solution was stirred 1 h at 25° C. The reactionwas monitored by TLC (PE:EA=4:1). The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withPE:EA=4:1 to yield1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-olas a light yellow oil.

Step 2:3-(1-chloro-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridine

Into a 100-mL round-bottom flask, were placed1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-ol(200 mg, 0.615 mmol, 1 equiv.), DCM (8 mL), SOCl₂ (122 mg, 1.233 mmol, 2equiv.). The resulting solution was stirred 1 h at 25° C. The reactionwas monitored by TLC (PE:EA=4:1). The resulting mixture was concentratedunder vacuum to yield3-(1-chloro-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridineas a light yellow oil.

Step 3:N-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-4H-1,2,4-triazol-3-amineand4-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-4H-1,2,4-triazol-3-amineand1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-1H-1,2,4-triazol-3-amine

Into a 10-mL sealed tube purged were added3-(1-chloro-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridine(100 mg, 0.291 mmol, 1 equiv.), DMF (4 ml), 4H-1,2,4-triazol-3-amine (49mg, 0.583 mmol, 2 equiv.). The reaction was stirred 2 h at 140° C. Thereaction was monitored by LCMS. The reaction was then quenched by theaddition of water (10 mL), extracted with ethyl acetate and the organiclayers combined. The resulting mixture was concentrated under vacuum.The residue was applied onto a silica gel column with DCM:MeOH=10:1 toyield a mixture ofN-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-4H-1,2,4-triazol-3-amine,4-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-4H-1,2,4-triazol-3-amine,1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-1H-1,2,4-triazol-3-amineas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂FN₅O, 392.2 (M+H), found392.2.

Step 4:3-(1-(4H-1,2,4-triazol-3-ylamino)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-oneand3-(1-(3-amino-4H-1,2,4-triazol-4-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-oneand3-(1-(3-amino-1H-1,2,4-triazol-1-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

The title compounds were prepared according to the procedure asdescribed in Example 1 step 5 by demethylation ofN-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-4H-1,2,4-triazol-3-amine,4-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-4H-1,2,4-triazol-3-amine,1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-1H-1,2,4-triazol-3-amine with TMSCl/NaI toyield

3-(1-(4H-1,2,4-triazol-3-ylamino)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-oneas a white solid. ¹H NMR (300 MHz, CD₃OD) δ: 8.39 (s, 1H), 8.28 (s, 1H),8.03 (d, J=8.4 Hz, 1H), 7.80-7.88 (m, 2H), 7.73 (d, J=8.4 Hz, 1H),7.49-7.56 (m, 1H), 7.23-7.29 (m, 1H), 6.79 (d, J=7.5 Hz, 1H), 4.79-4.81(m, 1H), 2.85-2.97 (m, 1H), 0.99 (d, J=6.4 Hz, 3H), 0.92 (d, J=6.4 Hz,3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −124.32. Mass spectrum (ESI, m/z):Calculated for C₂₁H₂₀FN₅O, 378.2 (M+H), found 378.1.

3-(1-(3-amino-4H-1,2,4-triazol-4-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-oneas a white solid. ¹H NMR (300 MHz, CD₃OD) δ: 8.36 (s, 1H), 7.96-8.03 (m,1H), 7.79 (d, J=6.9 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.47-7.64 (m, 3H),7.22-7.29 (m, 1H), 6.72 (d, J=7.2 Hz, 1H), 4.33 (d, J=7.5 Hz, 1H),2.30-2.42 (m, 1H), 1.04 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H). ¹⁹FNMR (300 MHz, CD₃OD) δ: −124.46. Mass spectrum (ESI, m/z): Calculatedfor C₂₁H₂₀FN₅O, 378.2 (M+H), found 378.1.

and3-(1-(3-amino-1H-1,2,4-triazol-1-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-oneas an off white solid. ¹H NMR (300 MHz, CD₃OD) δ: 8.36 (s, 1H), 8.11 (s,1H), 7.97-8.05 (m, 2H), 7.80-7.82 (m, 1H), 7.73 (d, J=8.4 Hz, 1H),7.48-7.58 (m, 1H), 7.23-7.29 (m, 1H), 6.72 (d, J=7.2 Hz, 1H), 5.13 (d,J=11.0 Hz, 1H), 2.70-2.76 (m, 1H), 0.94 (d, J=6.4 Hz, 3H), 0.87 (d,J=6.4 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −124.40.

Calculated for C₂₁H₂₀FN₅O, 378.2 (M+H), found 378.1.

Example 136 Compound #157 and #68 and #1586-(8-fluoronaphthalen-2-yl)-3-(1-(2-iminothiazol-3(2H)-yl)-2-methylpropyl)pyridin-2(1H)-oneand3-(1-(2-aminothiazol-5-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-oneand6-(8-fluoronaphthalen-2-yl)-3-(2-methyl-1-(thiazol-2-ylamino)propyl)pyridin-2(1H)-one

The title compounds were prepared according to the procedure asdescribed in Example 135 by coupling3-(1-chloro-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridinewith thiazol-2-amine and followed by demethylation of the mixture of3-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)thiazol-2(3H)-imine,5-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)thiazol-2-amine,N-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)thiazol-2-amine with TMSCl/NaI in CH₃CN to yield the products

6-(8-fluoronaphthalen-2-yl)-3-(1-(2-iminothiazol-3(2H)-yl)-2-methylpropyl)pyridin-2(1H)-oneas a light yellow semi-solid ¹H NMR (400 MHz, DMSO-d₆) δ: 8.50 (s, 1H),8.00-7.10 (m, 2H), 7.82-7.84 (m, 1H), 7.54-7.63 (m, 2H), 7.37-7.42 (m,1H), 7.24 (s, 1H), 6.92-6.94 (m, 1H), 5.97 (brs, 1H), 4.93-4.96 (m, 1H),2.93-2.95 (m, 1H), 0.90 (d, J=6.4 Hz, 3H), 0.85 (d, J=6.4 Hz, 3H). ¹⁹FNMR (400 MHz, DMSO-d₆) δ: −122.35. Mass spectrum (ESI, m/z): Calculatedfor C₂₂H₂₀FN₃OS, 394.1 (M+H), found 394.1.

3-(1-(2-aminothiazol-5-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-oneas a light yellow solid ¹H NMR (400 MHz, DMSO-d₆) δ: 8.47 (s, 1H), 8.09(d, J=8.8 Hz, 1H), 7.96 (d, J=9.6 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H),7.58-7.60 (m, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.39-7.42 (m, 1H), 6.80-6.85(m, 1H), 6.73 (s, 1H), 6.65 (s, 2H), 3.90 (d, J=10.8 Hz, 1H), 2.32-2.35(m, 1H), 0.93 (d, J=6.4 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H). ¹⁹F NMR (400MHz, DMSO-d₆) δ: −122.29. Mass spectrum (ESI, m/z): Calculated forC₂₂H₂₀FN₃OS, 394.1 (M+H), found 394.1.

and6-(8-fluoronaphthalen-2-yl)-3-(2-methyl-1-(thiazol-2-ylamino)propyl)pyridin-2(1H)-oneas an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.48 (s, 1H), 8.10(d, J=8.4 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.82-7.88 (m, 2H), 7.56-7.60(m, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.38-7.43 (m, 1H), 6.95 (d, J=3.6 Hz,1H), 6.84-6.86 (m, 1H), 6.56 (d, J=3.6 Hz, 1H), 4.71-4.75 (m, 1H),2.19-2.24 (m, 1H), 0.93-0.95 (m, 6H). ¹⁹F NMR (400 MHz, DMSO-d₆) δ:−122.26. Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₀FN₃OS, 394.1(M+H), found 394.1.

Example 137 Compound #1623-(1-(2-amino-1H-imidazol-1-yl)-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 135 by coupling3-(1-chloro-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridinewith 2-nitro-1H-imidazole and followed by demethylation of1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-1H-imidazol-2-aminewith TMSCl/NaI in CH₃CN to yield the product as an off-white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.41 (s, 1H), 8.05 (d, J=8.8 Hz, 1H),7.82-7.88 (m, 2H), 7.75 (d, J=8.4 Hz, 1H), 7.53-7.57 (m, 1H), 7.26-7.29(m, 1H), 6.82 (s, 2H), 6.52 (s, 1H), 4.94 (d, J=11.6 Hz, 1H), 2.65-2.75(m, 1H), 1.00 (d, J=6.4 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H). ¹⁹F NMR (400MHz, CD₃OD) δ: −124.37. Mass spectrum (ESI, m/z): Calculated forC₂₂H₂₁FN₄O, 377.2 (M+H), found 377.1.

Example 138 Compound #1726-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(2-methyl-1-(4H-1,2,4-triazol-4-yl)propyl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 135 by coupling followed by demethylation to yield theproduct as a yellow solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.65 (s, 1H), 8.15 (s, 1H), 8.06 (d, J=7.5Hz, 2H), 7.81 (s, 1H), 7.21 (d, J=9.9 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H),5.47 (d, J=6.9 Hz, 1H), 4.51-4.59 (m, 2H), 2.83-2.91 (m, 1H), 1.53 (t,J=7.2 Hz, 3H), 1.03 (d, J=6.6 Hz, 3H), 0.85 (d, J=6.6 Hz, 3H). ¹⁹F NMR(300 MHz, CD₃OD) δ: −119.01. Mass spectrum (ESI, m/z): Calculated forC₂₀H₂₁FN₆O_(, 381.1) [M+H], found 381.1.

Example 139 Compound #1716-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(2-methyl-1-(1H-tetrazol-1-yl)propyl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 135 by coupling followed by demethylation to yield theproduct as a white solid.

¹H NMR (300 MHz, CD₃OD) δ:8.71 (s, 1H), 8.10 (s, 1H), 8.05 (d, J=7.5 Hz,1H), 7.78 (s, 1H), 7.16 (d, J=9.9 Hz, 1H), 6.79 (d, J=7.5 Hz, 1H), 6.17(d, J=7.5 Hz, 1H), 4.46-4.49 (m, 2H), 2.75-2.88(m, 1H), 1.47 (t, J=7.5Hz, 3H), 1.01 (d, J=6.6 Hz, 3H), 0.80 (d, J=6.6 Hz, 3H). ¹⁹F NMR (300MHz, CD₃OD) δ: −118.70. Mass spectrum (ESI, m/z): Calculated forC₁₉H₂₀FN₇O, 382.2 [M+H], found 382.0.

Example 140 Compound #1546-(8-fluoronaphthalen-2-yl)-3-(2-methyl-1-(2-oxoimidazolidin-1-yl)propyl)pyridin-2(1H)-one

Step 1:N1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)ethane-1,2-diamine

Into a 100-mL round-bottom flask, were placed1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-one (500 mg, 1.546 mmol, 1 equiv.),ethane-1,2-diamine (278 mg, 4.626 mmol, 3 equiv.), MeOH (8 mL), AcOH (2mL). The resulting solution was stirred 4 h at 50° C. NaBH₄ (294 mg,7.771 mmol, 1 equiv.) was added and the resulting solution was stirred 1h at 50° C. The reaction was monitored by TLC (PE:EA=1:1). The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with PE:EA=1:1 to yieldN1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)ethane-1,2-diamine was obtained as light a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₆FN₃O, 368.2 (M+H), found368.2.

Step 2:1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)imidazolidin-2-one

Into a 100-mL round-bottom flask, were placedN1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)ethane-1,2-diamine(500 mg, 1.361 mmol, 1 equiv.), di(1H-pyrrol-1-yl)methanone (326 mg,2.035 mmol, 1.5 equiv.), TEA (757 mg, 7.481 mmol, 5.5 equiv.), CHCl₃ (10mL). The resulting solution was stirred overnight at 70° C. The reactionwas monitored by TLC (PE:EA=1:1). The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withPE:EA=1:1 to yield a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₄FN₃O₂, 394.5 (M+H), found394.2.

Step 3:6-(8-fluoronaphthalen-2-yl)-3-(2-methyl-1-(2-oxoimidazolidin-1-yl)propyl)pyridin-2(1H)-one

Into a 50-mL round-bottom flask, were placed1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)imidazolidin-2-one(100 mg, 0.254 mmol, 1 equiv.), TMSCl (50 mg, 0.460 mmol, 2 equiv.), NaI(80 mg, 0.534 mmol, 2 equiv.), CH₃CN (8 mL). The resulting solution wasstirred 4 h at 25° C. The reaction was monitored by LCMS. The resultingmixture was concentrated under vacuum. The residue was purified byPrep-HPLC with the following conditions (1#-Waters 2767-5): Column,SunFire Prep C18, 5 um, 19*100 mm; mobile phase, Water of 0.05% NH₄CO₃and CH₃CN (20% CH₃CN up to 50% in 10 min, up to 100% in 2 min, down to20% in 2 min; Detector, 254 nm to yield6-(8-fluoronaphthalen-2-yl)-3-(2-methyl-1-(2-oxoimidazolidin-1-yl)propyl)pyridin-2(1H)-oneas as an off white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.45 (s, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.88(d, J=8.8 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.72 (d, J=7.2 Hz, 1H),7.54-7.59 (m, 1H), 7.29-7.33 (m, 1H), 6.78 (d, J=7.2 Hz, 1H), 4.57 (d,J=11.2 Hz, 1H), 3.52-3.67 (m, 2H), 3.37-3.40 (m, 2H), 2.76-2.82 (m, 1H),1.07 (d, J=6.8 Hz, 3H), 0.89 (d, J=6.8 Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD)δ: −124.47. Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂FN₃O₂, 380.2(M+H), found 380.0.

Example 141 Compound #170(E)-N-(1-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)imidazolidin-2-ylidene)cyanamide

Step 1:1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)imidazolidine-2-thione

Into a 100-mL round-bottom flask, were placed1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)imidazolidin-2-one(100 mg, 0.254 mmol, 1 equiv.), Lawesson's Reagent (514 mg, 1.271 mmol,5 equiv.), toluene (8 mL). The resulting solution was stirred overnightat 100° C. The reaction was monitored by TLC (PE:EA=3:1). The reactionwas then quenched by the addition of water (10 mL). extracted with ethylacetate and the organic layers combined. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with PE:EA=3:1 to yield1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)imidazolidine-2-thionewas obtained as a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₄FN₃OS, 410.2 (M+H), found410.2.

Step 2:6-(8-fluoronaphthalen-2-yl)-2-methoxy-3-(2-methyl-1-(2-(methylthio)-4,5-dihydroimidazol-1-yl)propyl)pyridine

Into a 50-mL round-bottom flask, were placed1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)imidazolidine-2-thione(60 mg, 0.147 mmol, 1 equiv.), CH₃I (42 mg, 0.296 mmol, 2 equiv.), MeOH(6 mL). The resulting solution was stirred overnight at 70° C. Thereaction was monitored by TLC (DCM:MeOH=10:1). The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with DCM:MeOH=10:1 to yield6-(8-fluoronaphthalen-2-yl)-2-methoxy-3-(2-methyl-1-(2-(methylthio)-4,5-dihydroimidazol-1-yl)propyl)pyridineas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₆FN₃OS, 424.2 (M+H), found424.2.

Step 3:6-(8-fluoronaphthalen-2-yl)-3-(2-methyl-1-(2-(methylthio)-4,5-dihydroimidazol-1-yl)propyl)pyridin-2(1H)-one

Into a 50-mL round-bottom flask, were placed6-(8-fluoronaphthalen-2-yl)-2-methoxy-3-(2-methyl-1-(2-(methylthio)-4,5-dihydroimidazol-1-yl)propyl)pyridine(40 mg, 0.094 mmol, 1 equiv.), TMSCl (10 mg, 0.092 mmol, 2 equiv.), NaI(14 mg, 0.093 mmol, 2 equiv.), CH₃CN (4 ml). The resulting solution wasstirred overnight at 25° C. The reaction was monitored by TLC(PE:EA=10:1). The reaction was then quenched by the addition of water(10 mL). The mixture was then extracted with ethyl acetate and theorganic layers combined. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column withDCM:MeOH=10:1 to yield6-(8-fluoronaphthalen-2-yl)-3-(2-methyl-1-(2-(methylthio)-4,5-dihydroimidazol-1-yl)propyl)pyridin-2(1H)-one was obtained as a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₄FN₃OS, 410.2 (M+H), found410.0.

Step 4:(E)-N-(1-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)imidazolidin-2-ylidene)cyanamide

Into a 50-mL round-bottom flask, were placed6-(8-fluoronaphthalen-2-yl)-3-(2-methyl-1-(2-(methylthio)-4,5-dihydroimidazol-1-yl)propyl)pyridin-2(1H)-one(30 mg, 0.073 mmol, 1 equiv.), cyanamide (15 mg, 0.357 mmol, 5 equiv.),K₂CO₃ (51 mg, 0.369 mmol, 5 equiv.), 1,4-dioxane (5 mL). The resultingsolution was stirred overnight at 100° C. The reaction was monitored byLCMS. The resulting mixture was concentrated under vacuum. The residuewas purified by Prep-HPLC with the following conditions (1#-Waters2767-5): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, Waterof 0.05% NH₄CO₃ and CH₃CN (20% CH₃CN up to 50% in 10 min, up to 100% in2 min, down to 20% in 2 min; Detector, 254 nm to yield(E)-N-(1-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)imidazolidin-2-ylidene)cyanamide as a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.45 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.88(d, J=8.8 Hz, 1H), 7.74-7.80 (m, 2H), 7.55-7.60 (m, 1H), 7.29-7.34 (m,1H), 6.81 (d, J=7.2 Hz, 1H), 4.70 (d, J=11.2 Hz, 1H), 3.67-3.80 (m, 2H),3.50-3.60 (m, 2H), 2.78-2.83 (m, 1H), 1.07 (d, J=6.8 Hz, 3H), 0.90 (d,J=6.8 Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −124.42. Mass spectrum (ESI,m/z): Calculated for C₂₃H₂₂FN₅O, 404.2 (M+H), found 404.2.

Example 142 Compound #666-(8-fluoronaphthalen-2-yl)-3-(3-methyl-1-morpholinobutan-2-yl)pyridin-2(1H)-one

Step 1:4-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)morpholine

Into a 50-mL round-bottom flask, were placed a solution of2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanal(100 mg, 0.297 mmol, 1.00 equiv.), morpholine (51.6 mg, 0.593 mmol, 2.00equiv.), sodium triacetoxyborohydride (STAB) (119.8 mg, 0.593 mmol, 2.00equiv.) in THF (15 mL). AcOH (0.1 mL) was then added to the solution.The resulting solution was stirred for 2 h at 20° C. and the reactionwas monitored by LCMS. Water (10 ml) was added to the mixture and themixture was extracted with EA. The resulting mixture was evaporatedunder reduced pressure. The residue was applied onto a silica gel columnwith ethyl acetate/petroleum ether (1:5) to yield a residue.

Mass spectrum (EI, m/z): Calculated for C₂₅H₂₉FN₂O₂, 409.2 (M+H), found409.2.

Step 2:6-(8-fluoronaphthalen-2-yl)-3-(3-methyl-1-morpholinobutan-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation to yield the product as a whitesolid.

¹H NMR (400 MHz, CD₃OD) δ: 8.43 (s, 1 H), 8.08 (d, J=8.8 Hz, 1 H), 7.88(d, J=6.8 Hz, 1 H), 7.78 (d, J=8.4 Hz, 1 H), 7.53-7.57 (m, 2 H),7.28-7.32 (m, 1 H), 6.80 (d, J=7.2 Hz, 1 H), 3.50-3.67 (m, 4 H),3.12-3.15 (m, 1 H), 2.85 (t, J=11.2, 1 H), 2.57-2.66 (m, 3 H), 2.38-2.60(m, 2 H), 1.99-2.06 (m, 1 H), 1.02 (d, J=6.8 Hz, 3 H), 0.91 (d, J=6.8Hz, 3 H). Mass spectrum (EI, m/z): Calculated for C₂₄H₂₇FN₂O₂, 395.2(M+H), found 395.1.

Example 143 Compound #1156-(8-fluoronaphthalen-2-yl)-3-(3-methyl-1-(2-oxopiperidin-1-yl)butan-2-yl)pyridin-2(1H)-one

Step 1:2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-1-amine

Into a 50 mL round bottle flask, were placed2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-1-amine(600 mg, 1.778 mmol, 1 equiv.), CH₃OH (10 mL), NH₄OAc (1.4 g, 18 mmol,10 equiv.), NaBH₃CN (832 mg, 7 mmol, 4 equiv.). The solution was stirredfor 16 h at 70° C. The reaction progress was monitored by TLC/LCMS. Thereaction was quenched with H₂O. The resulting solution was extractedwith ethyl acetate (2×100 mL) and the organic layer was combined. Theresidue product was purified by TLC with D/M (1:10) to yield2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-1-amineas a colorless oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₃FN₂O, 339.2 (M+H), found339.2.

Step 2:5-bromo-N-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)pentanamide

Into a 50-mL round bottle flask, were placed 5-bromopentanoyl chloride(884 mg, 4.432 mmol, 3 equiv.), DMAP (746 mg, 3.694 mmol, 2.5 equiv.).CH₂Cl₂ (15 mL) was added. The solution was stirred for 30 min at 0° C.2-(6-(8-Fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-1-amine(500 mg, 1.477 mmol, 1 equiv.) in CH₂Cl₂ (2 mL) was added dropwise. Thesolution was stirred for 16 h at 50° C. The reaction was monitored withTLC/LCMS. The reaction was then quenched by ice water (5 mL). Theresulting solution was extracted with CH₂Cl₂ (2×100 mL) and the organiclayers were combined. The organic phase was concentrated undervacuum/the solvent was removed (to 5 ml) under vacuum. The residueproduct was purified by chromatogram on silica gel with ethylacetate/petroleum ether (1:5) to yield5-bromo-N-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)pentanamideas a colorless oil.

Mass spectrum (ESI, m/z): Calculated for C₂₆H₃₀BrFN₂O₂, 501.2 (M+H),found 501.2.

Step 3:1-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)piperidin-2-one

Into a 50-mL round bottle flask, were placed5-bromo-N-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)pentanamide(300 mg, 0.120 mmol, 1 equiv.), CH₃CN (15 mL). t-BuOK (0.48 mL, 0.48mmol, 4 equiv.) was then added dropwise and the reaction mixture wasstirred for 16 h at 50° C. The reaction was monitored with TLC/LCMS. Thereaction was quenched with H₂O. The resulting solution was extractedwith ethyl acetate (2×100 ml) and the organic layer was combined. Theresidue product was purified by TLC with P/E (1:10) to yield1-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)piperidin-2-oneas a colorless oil.

Mass spectrum (ESI, m/z): Calculated for C₂₆H₂₉FN₂O₂, 421.2 (M+H), found421.1.

Step 4:6-(8-fluoronaphthalen-2-yl)-3-(3-methyl-1-(2-oxopiperidin-1-yl)butan-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation to yield the product as a yellowsolid.

¹H NMR (300 MHz, CD₃OD) δ: 8.42 (s, 1H), 8.06 (d, J=7.8 Hz, 1H),7.84-7.87 (m, 2H), 7.51-7.58 (m, 2H), 7.26-7.32 (m, 1H), 6.75 (d, J=6.6Hz, 1H), 3.99-4.07 (m, 1H), 3.52-3.58 (m, 1H), 3.34-3.38 (m, 1H),3.11-3.15 (m, 2H), 2.09-2.29 (m, 3H), 1.60-1.66 (m, 4H), 1.07 (d, J=6.6Hz, 3H), 0.87 (d, J=6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calculatedfor C_(28.14)H_(28.57)F_(5.71)N₂O_(5.14), 407.2 (M+H−1.571.57CF₃COOH),found 407.0.

Example 144 Compound #23-(1-(cyclohexylsulfonyl)-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

Step 1:3-(1-chloro-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridine

Into a 100-mL round-bottom flask, were placed2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutan-1-ol(100 mg, 0.295 mmol, 1 equiv.), SOCl₂ (145 mg, 1.473 mmol, 5 equiv.),DCM (5 mL). The resulting solution was stirred overnight at 50° C. Thereaction was monitored by LCMS. The resulting mixture was concentratedunder vacuum to yield3-(1-chloro-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridineas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₁ClFNO, 358.1 (M+H), found357.9.

Step 2:3-(1-(cyclohexylthio)-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridine

Into a 50-mL round-bottom flask, were placed3-(1-chloro-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridine(60 mg, 0.168 mmol, 1 equiv.), DMF (5 mL), NaH (20 mg, 0.838 mmol, 5equiv.), cyclohexanethiol (58 mg, 0.503 mmol, 5 equiv.). The resultingsolution was stirred overnight at 25° C. The reaction was monitored byTLC (PE:EA=6:1). The reaction was then quenched by the addition of water(10 mL), extracted with ethyl acetate and the organic layers combined.The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column with PE:EA=6:1 to yield3-(1-(cyclohexylthio)-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridineas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₇H₃₂FNOS, 438.2 (M+H), found438.2.

Step 3:3-(1-(cyclohexylsulfonyl)-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridine

Into a 50-mL round-bottom flask, were placed3-(1-(cyclohexylthio)-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridine(60 mg, 0.137 mmol, 1 equiv.), H₂O₂(0.5 mL), AcOH (2 mL). The resultingsolution was stirred overnight at 25° C. The reaction was monitored byLCMS. The reaction was then quenched by the addition of 10 mL ofNa₂S₂O₃, extracted with ethyl acetate and the organic layers combined.The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column with PE:EA=2:1 to yield3-(1-(cyclohexylsulfonyl)-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridineas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₇H₃₂FNO₃S, 470.2 (M+H), found470.0.

Step 4:3-(1-(cyclohexylsulfonyl)-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation of3-(1-(cyclohexylsulfonyl)-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridine with TMSCl/NaIto yield the product as an off-white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.40 (s, 1H), 8.07 (d, J=7.2 Hz, 1H), 7.86(d, J=8.7 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.52-7.61 (m, 2H), 7.27-7.33(m, 1H), 6.78 (d, J=7.5 Hz, 1H), 3.86-3.95 (m, 1H), 3.10-3.20 (m, 1H),2.85-2.90 (m, 1H), 2.20-2.30 (m, 1H), 2.00-2.09 (m, 2H), 1.85-1.95 (m,2H), 1.65-1.70 (m, 1H), 1.23-1.46 (m, 6H), 1.05 (d, J=6.6 Hz, 3H), 0.90(d, J=6.6 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −124.52. Mass spectrum(ESI, m/z): Calculated for C₂₆H₃₀FNO₃S, 456.2 (M+H), found 456.3.

Example 145 Compound #165N-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)cyclohexanesulfonamide

Into a 50-mL round-bottom flask, were placed3-(1-amino-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one(30 mg, 0.096 mmol, 1 equiv.), THF (2 mL), DCM (2 mL),cyclohexanesulfonyl chloride (35 mg, 0.192 mmol, 2 equiv.), pyridine (15mg, 0.192 mmol, 2 equiv.). The resulting solution was stirred overnightat 25° C. The reaction was monitored by LCMS. The resulting mixture wasconcentrated under vacuum. The residue was purified by Prep-HPLC withthe following conditions (1#-Waters 2767-5): Column, SunFire Prep C18, 5um, 19*100 mm; mobile phase, Water of 0.05% NH₄HCO₃ and CH₃CN (20% CH₃CNup to 50% in 10 min, up to 100% in 2 min, down to 20% in 2 min;Detector, 254 nm to yieldN-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)cyclohexanesulfonamide as an off white semi-solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.42 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.87(d, J=8.4 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.70 (d, J=6.8 Hz, 1H),7.56-7.60 (m, 1H), 7.29-7.34 (m, 1H), 6.84 (d, J=7.2 Hz, 1H), 4.28 (d,J=8.4 Hz, 1H), 2.68-2.77 (m, 1H), 2.15-2.20 (m, 2H), 1.94-1.97 (m, 1H),1.83-1.86 (m, 1H), 1.75-1.78 (m, 1H), 1.62-1.65 (m, 1H), 1.19-1.50 (m,4H), 1.04-1.44 (m, 4H), 0.94 (d, J=6.4 Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD)δ: −124.48. Mass spectrum (ESI, m/z): Calculated for C₂₅H₂₉FN₂O₃S, 457.2(M+H), found 457.2.

Example 146 Compound #1666-(8-fluoronaphthalen-2-yl)-3-(2-methyl-1-(2-oxopiperidin-1-yl)propyl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 143 by coupling of1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-aminewith 5-bromopentanoyl chloride, cyclization and demethylation to yieldthe product as a yellow solid as an off-white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.44 (s, 1H), 8.08 (d, J=8.8 Hz, 1H),7.78-7.79 (m, 3H), 7.54-7.60 (m, 1H), 7.29-7.34 (m, 1H), 6.81 (d, J=7.2Hz, 1H), 5.19-5.21 (m, 1H), 3.46-3.49 (m, 1H), 3.24-3.28 (m, 1H),2.77-2.86 (m, 1H), 2.36-2.40 (m, 2H), 1.71-1.81 (m, 4H), 1.04 (d, J=6.4Hz, 3H), 0.94 (d, J=6.4 Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −124.47.Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₅FN₂O₂, 393.2 (M+H), found393.0.

Examples 147 Compound #1636-(8-fluoronaphthalen-2-yl)-3-(2-methyl-1-(2-oxopiperidin-1-yl)propyl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 143 by coupling of1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-amineand 4-chlorobutane-1-sulfonyl chloride, cyclization and demethylation toyield the product as an off-white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.42 (s, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.89(d, J=8.7 Hz, 1H), 7.74-7.80 (m, 2H), 7.53-7.60 (m, 1H), 7.27-7.33 (m,1H), 6.81 (d, J=7.2 Hz, 1H), 4.74 (d, J=11.4 Hz, 1H), 3.51-3.55 (m, 1H),3.33-3.40 (m, 1H), 3.10-3.15 (m, 1H), 3.01-3.04 (m, 1H), 2.51-2.55 (m,1H), 2.00-2.20 (m, 2H), 1.45-1.55 (m, 1H), 1.18-1.22 (m, 1H), 1.13 (d,J=6.6 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ:−124.44. Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₅FN₂O₃S, 429.2(M+H), found 429.2.

Example 148 Compound #1683-(1-(1,1-dioxidothiomorpholino)-2-methylpropyl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

Step 1:6-(5-(1-chloro-2-methylpropyl)-6-methoxypyridin-2-yl)-1-ethyl-4-fluoro-1H-indazole

Into a 100-mL round-bottom flask, were placed1-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-ol(150 mg, 2.184 mmol, 1.00 equiv.), DCM (8 mL), SOCl₂ (216 mg, 0.728mmol, 5.00 equiv.). The reaction was stirred 2 h at 25° C. The reactionwas monitored by TLC (PE:EA=3:1). The resulting mixture was concentratedunder vacuum to yield6-(5-(1-chloro-2-methylpropyl)-6-methoxypyridin-2-yl)-1-ethyl-4-fluoro-1H-indazoleas a light yellow oil.

Step 2:4-(1-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)thiomorpholine

Into a 10-mL sealed tube purged was6-(5-(1-chloro-2-methylpropyl)-6-methoxypyridin-2-yl)-1-ethyl-4-fluoro-1H-indazole(150 mg, 0.415 mmol, 1.00 equiv.), thiomorpholine (428 mg, 4.145 mmol,10.00 equiv.), DIEA (536 mg, 4.145 mmol, 10.00 equiv.), CuI (79 mg,0.415 mmol, 1.00 equiv.), NMP (5 mL). The reaction was stirred 2 h at180° C. by microwave. The reaction was monitored by TLC (PE:EA=3:1). Thereaction was then quenched by saturation NaHCO₃ solution. The resultingsolution was extracted with EA. The organic layer was washed with water,dried (magnesium sulfate), and concentrated.

The residue was applied onto a silica gel column with PE:EA=3:1 to yield4-(1-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)thiomorpholineas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₉FN₄OS, 429.1 [M+H], found429.4.

Step 3:4-(1-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)thiomorpholine 1,1-dioxide

Into a 50-mL round-bottom flask, were placed4-(1-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)thiomorpholine(120 mg, 0.280 mmol, 1.00 equiv.), potassium peroxydisulfate (151 mg,0.560 mmol, 2.00 equiv.), EA (5 mL), H₂O (3 mL). The reaction wasstirred 4 h at 25° C. The reaction was monitored by LCMS. The reactionwas then quenched by saturation NaHCO₃ solution. The resulting solutionwas extracted with EA.

The organic layer was washed with water, dried (magnesium sulfate), andconcentrated. The residue was applied onto a silica gel column withPE:EA=3:1 to yield4-{1-[6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl]-2-methylpropyl}-1λ6,4-thiomorpholine-1,1-dioneas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₉FN₄O₃S, 461.1 [M+H],found 461.1.

Step 4:3-(1-(1,1-dioxidothiomorpholino)-2-methylpropyl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation to yield the product as a whitesolid.

¹H NMR (400 MHz, CD₃OD) δ: 8.16 (s, 1H), 7.84 (s, 1H), 7.56 (d, J=7.2Hz, 1H), 7.22 (d, J=12.0 Hz, 1H), 6.80 (d, J=7.2 Hz, 1H), 4.54-4.60 (m,2H), 3.85 (d, J=11.2 Hz, 1H), 3.04-3.09 (m, 6H), 2.93-2.94 (m, 2H),2.31-2.36 (m, 1H), 1.53-1.56 (m, 3H), 1.17 (d, J=6.4 Hz, 3H), 0.92 (d,J=6.4 Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −119.11. Mass spectrum (ESI,m/z): Calculated for C₂₂H₂₇FN₄O₃S, 447.1 [M+H], found 447.1.

Example 149 Compound #280 and #281 ethyl2-(cyclohex-1-en-1-yl)-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetateand ethyl2-cyclohexylidene-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetate

Step 1: ethyl2-(cyclohex-1-en-1-yl)-2-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)acetateand ethyl2-cyclohexylidene-2-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)acetate

The title compounds were prepared according to the procedure asdescribed in Example 43 step 1 and 2 by coupling with ethyl2-cyclohexyl-2-oxoacetate followed by de-hydroxylation with pTSA toyield the products as a colorless oil.

Mass spectrum (ESI, m/z): Calculated for C₂₆H₂₇NO₃, 402.51 (M+H), found402.5.

Step 2: ethyl2-(cyclohex-1-en-1-yl)-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetateand ethyl2-cyclohexylidene-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetate

The title compounds were prepared according to the procedure asdescribed in Example 1 step 5 by demethylation to yield

Ethyl2-(cyclohex-1-en-1-yl)-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetateas a clear oil. ¹H NMR (400 MHz, CDCl₃) δ: 12.4 (br, s, 1H), 8.32 (s,1H), 8.05 (d, J=6.5 Hz, 1 H), 7.95 (d, J=7.5 Hz, 1H), 7.88 (d, J=6.5 Hz,2H), 7.55 (m, 3H), 6.69 (d, J=7.0 Hz, 1H), 5.65 (s, 1H), 4.62 (s, 1H),4.10 (m, 2H), 2.10 (4H), 1.65 (m, 4H), 1.18 (t, J=7.8 Hz, 3H). Massspectrum (ESI, m/z): Calculated for C₂₂H₁₉FN₂O₂, 388.48 (M+H), found388.5.

and Ethyl2-cyclohexylidene-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetateas a clear oil. ¹H NMR (400 MHz, CDCl₃) δ: 11.4 (br, s, 1H), 8.30 (s,1H), 8.05 (d, J=7.5 Hz, 1 H), 7.90 (m, 1H), 7.82 (m, 1H), 7.55 (d, J=7.0Hz, 2H), 7.38 (d, J=7.8 Hz, 1H), 6.67 (d, J=7.1 Hz, 1H), 4.12 (q, J=6.2Hz, 2H), 2.62 (m, 2H), 2.20 (m, 2H), 1.72 (m, 2H), 1.55 (m, 4H), 1.15(t, J=7.0 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₂H₁₉FN₂O₂,388.48 (M+H), found 388.6.

Example 150 Compound #1693-(1-(1,1-dioxidothiomorpholino)-2-methylpropyl)-6-(4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 149 by coupling and demethylation to yield the product as anoff-white solid.

¹H NMR (300 MHz, CD₃OD) δ: 7.49 (d, J=7.2 Hz, 1H), 7.00 (s, 1H),6.89-6.92 (m, 1H), 6.81 (d, J=8.1 Hz, 1H), 6.59 (d, J=7.5 Hz, 1H),4.27-4.30 (m, 2H), 3.82 (d, J=11.1 Hz, 1H), 3.45-3.50 (m, 2H), 3.37-3.40(m, 2H), 2.92-3.33 (m, 8H), 2.30 (brs, 1H), 1.15-1.24 (m, 6H), 0.81 (d,J=6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₃H₃₁N₃O₄S,446.1 [M+H], found 446.0.

Example 151 Compound #1646-(4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(2-methyl-1-thiomorpholinopropyl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 149 by coupling and demethylation to yield the product as anoff-white solid.

¹H NMR (300 MHz, CD₃OD) δ: 7.45 (d, J=7.2 Hz, 1H), 7.00 (s, 1H),6.89-6.92 (m, 1H), 6.81 (d, J=8.1 Hz, 1H), 6.59 (d, J=7.5 Hz, 1H),4.27-4.30 (m, 2H), 3.82 (d, J=11.1 Hz, 1H), 3.45-3.50 (m, 2H), 3.37-3.40(m, 2H), 2.62-2.70 (m, 8H), 2.20 (brs, 1H), 1.11-1.24 (m, 6H), 0.78 (d,J=6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₃H₃₁N₃O₂S,414.1 [M+H], found 414.0.

Example 152 Compound #1334-{2-[6-(1-ethyl-4-fluoroindazol-6-yl)-2-oxo-1H-pyridin-3-yl]-3-methylbutyl},4-thiomorpholine-1,1-dione

Step 1:4-(2-(2-methoxy-6-methylpyridin-3-yl)-3-methylbutyl)thiomorpholine

To a rapidly stirred solution of2-(2-methoxy-6-methylpyridin-3-yl)-3-methylbutanal (500 mg, 2.410 mmol,1.00 equiv.) in THF (20 mL) under N₂ atmosphere, was addedthiomorpholine (430 mg, 4.170 mmol, 1.73 equiv), CH₃COOH (1 mL), andthen NaBH(OAc)₃ (930 mg, 4.390 mmol, 2.00 equiv.) dropwise. The reactionwas stirred 2 h at 25° C. The reaction was monitored by LCMS. Theresulting solution was extracted with EtOAc, then the organic layerscombined and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:10) to yield4-(2-(6-chloro-2-methoxypyridin-3-yl)-3-methylbutyl)thiomorpholine as acolorless oil.

Mass spectrum (ESI, m/z): Calculated for C₁₆H₂₆N₂₀S, 315.1 [M+H], found315.2.

Step 2:4-{2-[6-(1-ethyl-4-fluoroindazol-6-yl)-2-oxo-1H-pyridin-3-yl]-3-methylbutyl},4-thiomorpholine-1,1-dione

The title compound was prepared according to the procedure as describedin Example 149 by oxidation and demethylation to yield the product as anoff-white solid.

¹H NMR (400 MHz, Methanol-d₄) δ: 8.13 (s, 1H), 7.80 (s, 1H), 7.49 (d,J=7.2 Hz, 1H), 7.18-7.21 (m, 1 H), 6.75 (d, J=7.2 Hz, 1H), 4.51-4.57 (m,2H), 2.84-3.09 (m, 11H), 2.01-2.03 (m, 1H), 1.52 (t, J=6.4 Hz, 3H), 1.01(d, J=6.8 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H). ¹⁹F NMR (400 MHz,Methanol-d₄) δ: −119.19. Mass spectrum (ESI, m/z): Calculated forC₂₃H₂₉FN₄O₃S, 461.2[M+H], found 461.3.

Example 153 Compound #1043-(1-(1,1-dioxidothiomorpholino)-3-methylbutan-2-yl)-6-(4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 149 by coupling and demethylation to yield the product as anoff-white solid.

¹H NMR (400 MHz, Methanol-d₄) δ 7.42 (d, J=7.6 Hz, 1 H), 6.96 (s, 1 H),6.86 (d, J=10.4 Hz, 1 H), 6.78 (d, J=8.4 Hz, 1 H), 6.53 (d, J=7.2 Hz, 1H), 4.21-4.26 (m, 2 H), 3.45-3.47 (m, 2 H), 3.34-3.36 (m, 2 H),2.79-3.15 (m, 11 H), 1.96-2.01 (s, 1 H), 1.17-1.20 (m, 3 H), 0.99 (d,J=6.7 Hz, 3 H), 0.85 (d, J=6.7 Hz, 3 H). Mass spectrum (ESI, m/z): Calcdfor C₂₄H₃₃N₃O₄S, 460.2 (M+H), found 460.1.

Example 154 Compound #1096-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-methyl-1-(4-(methylsulfonyl)piperazin-1-yl)butan-2-yl)pyridin-2(1H)-one

Step 1: tert-butyl4-(2-(6-chloro-2-methoxypyridin-3-yl)-3-methylbutyl)piperazine-1-carboxylate

Into a 100-ml round-bottom flask, were placed a solution of2-(6-chloro-2-methoxypyridin-3-yl)-3-methylbutanal (300 mg, 1.318 mmol,1.00 equiv.) and tert-butyl piperazine-1-carboxylate (269.94 mg, 1.449mmol, 1.10 equiv.) in THF (10 mL). Acetic acid (2.37 mg, 0.040 mmol,0.03 equiv.) was then added. After 15 min sodium triacetoxyborohydride(558.51 mg, 2.635 mmol, 2.00 equiv.) was added. The solution was stirredovernight at room temperature. The reaction was monitored by LCMS. Theresulting solution was extracted with EtOAc, then the organic layerscombined and concentrated under vacuum. The residue was applied onto asilica gel column with PE:EA=10:1 to yield tert-butyl4-(2-(6-chloro-2-methoxypyridin-3-yl)-3-methylbutyl)piperazine-1-carboxylateobtained as a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₀H₃₂ClN₃O₃, 398.2 [M+H],found 398.1.

Step 2: tert-butyl4-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)piperazine-1-carboxylate

Into a sealed tube purged and maintained with an inert atmosphere ofnitrogen, were placed a solution of tert-butyl4-(2-(6-chloro-2-methoxypyridin-3-yl)-3-methylbutyl)piperazine-1-carboxylate(240 mg, 0.603 mmol, 1.00 equiv.),1-ethyl-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(209.98 mg, 0.724 mmol, 1.20 equiv.), Pd(PPh₃)₄(34.85 mg, 0.030 mmol,0.05 equiv.), tetrabutylammonium bromide (194.42 mg, 0.603 mmol, 1.00equiv.), sodium carbonate (127.84 mg, 1.206 mmol, 2.00 equiv.) in DME(10 mL) and water (2 mL). The resulting solution was irradiated withmicrowave radiation for 20 min at 140° C. The reaction was monitored byLCMS. The resulting solution was extracted with EtOAc, then the organiclayers combined and concentrated under vacuum. The residue was appliedonto a silica gel column with PE:EA=8:1 to yield tert-butyl4-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)piperazine-1-carboxylateas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₉H₄₀FN₅O₃, 526.3 [M+H], found526.3.

Step 3:1-ethyl-4-fluoro-6-(6-methoxy-5-(3-methyl-1-(piperazin-1-yl)butan-2-yl)pyridin-2-yl)-1H-indazole

Into a 25-mL round-bottom flask, were placed a solution of tert-butyl4-(2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylbutyl)piperazine-1-carboxylate(180 mg, 0.342 mmol, 1.00 equiv.) in DCM (6 mL). Trifluoroacetic acid (1mL) was then added. The solution was stirred overnight at roomtemperature. The reaction was monitored by LCMS. The resulting solutionwas adjusted to pH 6˜7 with sodium bicarbonate and then extracted withEtOAc. The organic layers combined and concentrated under vacuum. Theresidue was applied onto a silica gel column with DCM:MeOH=30:1 to yield1-ethyl-4-fluoro-6-(6-methoxy-5-(3-methyl-1-(piperazin-1-yl)butan-2-yl)pyridin-2-yl)-1H-indazoleas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₃₂FN₅O, 426.3 [M+H], found426.3.

Step 4:1-ethyl-4-fluoro-6-(6-methoxy-5-(3-methyl-1-(4-(methylsulfonyl)piperazin-1-yl)butan-2-yl)pyridin-2-yl)-1H-indazole

Into a 25-ml round-bottom flask, were placed a solution of1-ethyl-4-fluoro-6-(6-methoxy-5-(3-methyl-1-(piperazin-1-yl)butan-2-yl)pyridin-2-yl)-1H-indazole(110 mg, 0.258 mmol, 1.00 equiv.) in DCM (10 mL). Then methanesulfonylchloride (59.22 mg, 0.517 mmol, 2.00 equiv.) and triethylamine (52.31mg, 0.517 mmol, 2.00 equiv.) were added. The solution was stirred for5.0 h at room temperature. The reaction was monitored by LCMS. Theresulting solution was extracted with DCM, then the organic layerscombined and concentrated under vacuum. The residue was applied onto asilica gel column with PE:EA=1:1 to yield1-ethyl-4-fluoro-6-(6-methoxy-5-(3-methyl-1-(4-(methylsulfonyl)piperazin-1-yl)butan-2-yl)pyridin-2-yl)-1H-indazoleas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₅H₃₄FN₅O₃S, 504.2 [M+H],found 504.2.

Step 5:6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-methyl-1-(4-(methylsulfonyl)piperazin-1-yl)butan-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 149 by demethylation to yield the product as a yellow solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.15 (s, 1H), 7.81 (s, 1H), 7.52 (d, J=7.2Hz, 1 H), 7.21 (d, J=9.9 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 4.53-4.60 (m,2H), 3.09-3.16 (m, 4H), 2.80-3.09 (m, 4H), 2.52-2.74 (m, 2 H), 2.41-2.51(m, 2H), 2.01-2.04 (m, 1H), 1.54 (t, J=7.2 Hz, 3H), 1.03 (d, J=6.9 Hz,3H), 0.90 (d, J=6.9 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −119.16. Massspectrum (ESI, m/z): Calculated For C₂4H₃₂FN₅O₃S, 490.2 [M+H], found490.2.

Example 155 Compound #1294-{2-[6-(4-ethyl-8-fluoro-2,3-dihydro-1,4-benzoxazin-6-yl)-2-oxo-1H-pyridin-3-yl]-3-methylbutyl}-1,4-thiomorpholine-1,1-dione

Step 1: 5-bromo-2-(2-bromoethoxy)-1-fluoro-3-nitrobenzene

Into a 250-mL round bottle, to a solution of4-bromo-2-fluoro-6-nitrophenol (5.00 g, 21 mmol, 1.00 equiv.) in DMF (50mL). 1,2-Dibromoethane (5.90 g, 31 mmol, 1.50 equiv.), K₂CO₃ (5.80 g, 42mmol, 2.00 equiv.) were added and the mixture was stirred for 3 h at 80°C. The mixture was quenched by the addition of H₂O, extracted with EA,the organic layers was concentrated under vacuum. The residue purifiedby silica gel with ethyl acetate/petroleum ether (5:95). The collectedfractions were combined and concentrated under vacuum to yield5-bromo-2-(2-bromoethoxy)-1-fluoro-3-nitrobenzene as yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.79 (t, J=2.2 Hz, 1H), 7.56 (d, J=9.9 Hz,1H), 4.52 (t, J=6.4, Hz, 2H), 3.64-3.88 (m, 2H).

Step 2: 6-bromo-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine

Into a 100-mL round bottle, to a solution of5-bromo-2-(2-bromoethoxy)-1-fluoro-3-nitrobenzene (3.90 g, 11.000 mmol,1.00 equiv.) in EtOH (50 mL), were added Fe (3.00 g, 57 mmol, 5.00equiv.), NH₄Cl (3.00 g, 57 mmol, 5.00 equiv.), and the mixture wasstirred for 16 h at 80° C. The solid was filtered out, the organic layerwas concentrated under vacuum. The residue purified by silica gel withethyl acetate/petroleum ether (20:80). The collected fractions werecombined and concentrated under vacuum to yield6-bromo-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine as yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₈H₇BrFNO, 232.0 [M+H], found231.8.

Step 3: 6-bromo-4-ethyl-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine

Into a 20-mL vial, to a solution of6-bromo-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (300 mg, 1.300mmol, 1.00 equiv.) in THF (5 mL), was added NaBH₄CN (165 mg, 2.500 mmol,2.00 equiv.) with stirring at 0° C. Acetaldehyde (1 mL) and CH₃COOH (0.5mL) were then added and the mixture was stirred for 16 h at 70° C. Themixture was concentrated under vacuum. The residue purified by silicagel with ethyl acetate/petroleum ether (20:80). The collected fractionswere combined and concentrated under vacuum to yield6-bromo-4-ethyl-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine as yellowoil.

Mass spectrum (ESI, m/z): Calculated for C₁₀H₁₁BrFNO, 260.0 [M+H], found259.9.

Step 5:4-{2-[6-(4-ethyl-8-fluoro-2,3-dihydro-1,4-benzoxazin-6-yl)-2-oxo-1H-pyridin-3-yl]-3-methylbutyl}-1,4-thiomorpholine-1,1-dione

The title compound was prepared according to the procedure as describedin Example 149 by coupling and demethylation to yield the product asyellow solid.

¹H NMR (400 MHz, CD₃OD) δ 7.58 (d, J=7.4 Hz, 1H), 6.75-6.80 (m, 2H),6.38 (d, J=7.4 Hz, 1H), 4.16-4.27 (m, 2H), 3.71 (brs, 2H), 3.44-3.62 (m,3H), 3.27-3.45 (m, 9H), 3.06-3.13 (m, 1H), 2.11-2.16 (m, 1H), 1.10 (t,J=7.1 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.82 (d, J=6.6 Hz, 3H). ¹⁹F NMR(400 MHz, CD₃OD) δ −77.24, −138.0. Mass spectrum (ESI, m/z): Calculatedfor C_(36.44)H_(38.22)F_(19.66)N₃O_(16.44)S, 478.2 [M−6.22CF₃COOH+H],found 478.6.

Example 156 Compound #1284-{2-[6-(4-ethyl-8-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-2-oxo-1H-pyridin-3-yl]-3-methylbutyl},4-thiomorpholine-1,1-dione

Step 1: ethyl 2-(4-bromo-2-fluoro-6-nitrophenoxy)acetate

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed a 4-bromo-2-fluoro-6-nitrophenol(500 mg, 2.119 mmol, 1.00 equiv.) in DMF (10 mL), ethyl 2-bromoacetate(424 mg, 2.539 mmol, 1.20 equiv.) and K₂CO₃ (588 mg, 4.255 mmol, 2.00equiv.). The resulting solution was stirred 12 h at 60° C. The reactionwas monitored by TLC. The resulting solution was extracted with EtOAc,then the organic layers combined and concentrated under vacuum. Theresidue was applied onto a silica gel column with EA/PE (1:10) to yieldethyl 2-(4-bromo-2-fluoro-6-nitrophenoxy)acetate as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ: 7.79-7.77 (m, 1H), 7.52-7.49 (m, 1H), 4.80(s, 2 H), 4.27-4.22 (m, 2H), 1.32-1.26 (m, 3H

Step 2: 6-bromo-8-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed ethyl2-(4-bromo-2-fluoro-6-nitrophenoxy)acetate (408 mg, 1.267 mmol, 1.00equiv.) and Fe (415 mg, 7.431 mmol, 6.00 equiv.) in EtOH (10 mL). NH₄Cl(393 mg, 7.347 mmol, 6.00 equiv.) was added. The resulting solution wasstirred 12 h at 60° C. The reaction was monitored by LCMS. The resultingsolution was extracted with EtOAc, and the organic layers combined andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with EA/PE (1:10) to yield ethyl2-(4-bromo-2-fluoro-6-nitrophenoxy)acetate as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ: 7.00-9.67 (m, 1H), 6.76-6.75 (m, 1H), 4.68(s, 2 H).

Step 3: 6-bromo-4-ethyl-8-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed a6-bromo-8-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.203 mmol,1.00 equiv.) and iodoethane (57 mg, 0.365 mmol, 1.80 equiv.) in CH₃CN (5mL), K₂CO₃ (57 mg, 0.412 mmol, 2.00 equiv.) and benzyltriethylammoniumchloride (BTEAC) (46 mg, 0.203 mmol, 1.00 equiv.). The resultingsolution was stirred 12 h at 60° C. The reaction was monitored by TCLthe resulting solution was extracted with EtOAc, then the organic layerscombined and concentrated under vacuum. The residue was applied onto asilica gel column with EA/PE (1:10) to yield6-bromo-4-ethyl-8-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one as a yellowsolid.

¹H NMR (400 MHz, CDCl₃), δ: 7.06-7.02 (m, 1H), 6.95-6.94 (m, 1H), 4.68(s, 2 H), 4.02-0.95 (m, 2H), 1.33-1.28 (m, 3H).

Step 4:4-{2-[6-(4-ethyl-8-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-2-oxo-1H-pyridin-3-yl]-3-methylbutyl},4-thiomorpholine-1,1-dione

The title compound was prepared according to the procedure as describedin Example 149 by coupling and demethylation to yield the product as anoff-white solid.

¹H NMR (400 MHz, Methanol-d₄) δ: 7.60 (s, 1H), 7.31-7.26 (m, 2H), 6.72(d, J=7.2 Hz, 1H), 4.74 (s, 2 H), 4.12-4.11 (m, 2H), 3.77 (s, 2H),3.61-3.58 (m, 4 H), 3.48-3.31 (m, 4 H), 3.13-3.09 (m, 1H), 2.17-2.12 (m,1H), 1.31-1.27 (m, 3H), 0.90 (d, J=6.8 Hz, 3H), 0.79 (s, 3H). ¹⁹F NMR(400 MHz, Methanol-d₄) δ: −135.63, −77.36. Mass spectrum (ESI, m/z):Calculated for C₂₄H₃₀FN₃O₅S, 492.2 [M+H−1.32 CF₃COOH], found 492.2.

Example 157 Compound #1193-(1-(1,1-dioxidothiomorpholino)-3-methylbutan-2-yl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 149 by coupling and demethylation to yield the product as anoff-white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.40 (s, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.85(d, J=8.7 Hz, 1H), 7.74-7.80 (m, 2H), 7.52-7.58 (m, 1H), 7.25-7.35 (m,1H), 6.75 (d, J=7.2 Hz, 1H), 3.10 (m, 1H), 3.05 (m, 4H), 2.95 (m, 4H),2.84 (m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H). Massspectrum (ESI, m/z): Calculated for C₂₄H₂₇FN₂O₃S, 443.55 [M+H], found443.7.

Example 158 Compound #1016-(8-fluoronaphthalen-2-yl)-3-(3-methyl-1-(4-(methylsulfonyl)piperazin-1-yl)butan-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 149 by coupling and demethylation to yield the product as anoff-white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.35 (s, 1H), 7.98 (d, J=7.0 Hz, 1H), 7.75(d, J=8.5 Hz, 1H), 7.76 (m, 2H), 7.55 (m, 1H), 7.31 (m, 1H), 6.70 (d,J=7.0 Hz, 1H), 3.16 (m, 3H), 3.10 (m, 1H), 2.95 (m, 4H), 2.62 (m, 2 H),2.45 (m, 2H), 2.01-2.04 (m, 2H), 1.02 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5Hz, 3H).

Mass spectrum (ESI, m/z): Calculated for C₂₅H₃₀FN₃O₃S, 472.59 [M+H],found 472.7.

Example 159 Compound #2482-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-isopropylmorpholin-3-one

Step 1: ethyl2-(6-chloro-2-methoxypyridin-3-yl)-2-(cyanomethoxy)-3-methylbutanoate

Ethyl2-(6-chloro-2-methoxypyridin-3-yl)-2-(cyanomethoxy)-3-methylbutanoate(600 mg, 2.08 mmol, 1 equiv.) in DMF (5 mL) was treated with NaH (60%,125 mg, 3.13 mmol, 1.5 equiv.) for 10 min at 0° C. Bromoacetonitrile(139 μL, 2.08 mmol, 1 equiv.) was added dropwise and the reaction waswarmed to room temperature for 2 hour. The solution was partitionedbetween water and ethyl acetate. The organic layer was washed withbrine, dried and concentrated and purified by silica gel column to yieldthe product as a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₅H₁₉ClN₂O₄: 327.78 [M+H],found: 327.5.

Step 2: 2-(6-chloro-2-methoxypyridin-3-yl)-2-isopropylmorpholin-3-one

Ethyl2-(6-chloro-2-methoxypyridin-3-yl)-2-(cyanomethoxy)-3-methylbutanoate(150 mg, 0.46 mmol, 1 equiv.) and K₂CO₃ (317 mg, 2.295 mmol, 5 equiv.)in EtOH (10 mL) were refluxed overnight. The solvent was removed and theresidue was dissolved in EtOH (10 mL) and treated with PtO₂ (10 mg,0.046 mmol, 0.1 equiv.) under 50 psi hydrogenation overnight. Thecatalyst was filtrated and the residue was worked up to yield theresidue which was then purified by silica gel column to yield theproduct as a white solid.

Mass spectrum (ESI, m/z): Calculated for C₁₃H₁₇ClN₂O₃: 285.74 [M+H],found: 285.5.

Step 3:2-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-isopropylmorpholin-3-one

The title compound was prepared according to the procedure as describedin Example 1 step 1 by Suzuki coupling with1-ethyl-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazolefollowed by demethylation to yield the product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 10.05 (br, s, 1H), 8.11 (s, 1H), 7.98 (d,J=4.5 Hz, 1H), 7.92 (s, 1H0, 7.17 (s, 1H), 7.10 (d, J=7.2 Hz, 1H), 4.52(q, J=5.0 Hz, 2H), 4.08 (m, 2H), 3.78 (m, 2H), 3.70 (m, 1H), 3.38 (m,2H), 2.85 (m, 2H), 1.55 (t, J=7.0 Hz, 3H), 1.10 (d, J=6.0 Hz, 3H), 0.88(d, J=6.0 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₃FN₄O₃:399.44 [M+H], found: 399.5.

Example 160 Compound #2475-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxamide

Step 1: methyl 2-(6-chloro-2-methoxypyridin-3-yl)acrylate

Methyl 2-(6-chloro-2-methoxypyridin-3-yl)-2-hydroxypropanoate (1 g, 4.08mmol, 1 equiv.) in toluene (15 mL) was treated with pTSA (70 mg, 0.41mmol, 0.1 equiv.) and reflux overnight. The solution was partitionedwith ethyl acetate and saturated NaHCO₃ and then washed with brine,dried, concentrated to yield the residue which was used in the next stepwithout further purification.

Step 2: methyl5-(6-chloro-2-methoxypyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate

Methyl 2-(6-chloro-2-methoxypyridin-3-yl)acrylate (405 mg, 1.8 mmol, 1equiv.) and TMSCHN₂ (1.8 mL, 2.0 N, 3.6 mmol, 2 equiv.) in THF (10 mL)were heated to reflux overnight. The solvent was removed and the residuewas purified by silica gel column to yield the product as a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₁H₁₂ClN₃O₃: 270.69 [M+H],found: 270.5.

Step 3:5-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxamide

The title compound was prepared according to the procedure as describedin Example 1 step 1 by Suzuki coupling with naphthalen-2-ylboronic acidfollowed by hydrolysis, aminolysis and demethylation to yield theproduct as a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.21 (s, 1H), 8.02 (m, 3H), 7.95 (d, J=5.2Hz, 1H), 7.72 (m, 2H), 7.58 (d, J=7.2 Hz, 2H), 6.80 (m, 1H), 3.35 (m,2H).

Mass spectrum (ESI, m/z): Calculated for C₁₉H₁₆N₄O₂: 333.36 [M+H],found: 333.5.

Example 161 Compound #2525-((6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 by coupling, dehydration, hydrogenation and demethylationto yield the product as a white solid.

Mass spectrum (ESI, m/z): Calculated for C₁₉H₁₃FN₂O₄, 353.1 (M+H), found353.0.

Example 162 Compound #176-(4-ethyl-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(3-((2-oxopyrrolidin-3-yl)methyl)pentan-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 8 step 1 by hydrogenation and demethylation to yield theproduct as a white solid.

Mass spectrum (ESI, m/z): Calculated for C₂₅H₃₂FN₃O₃, 442.5 (M+H), found442.2.

Example 163 Compound #124(Z)-5-(2-(6-(1-cyclopentyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutylidene)oxazolidine-2,4-dione

The title compound was prepared according to the procedure as describedin Example 5 starting with aldol condensation by t-BuLi, dehydrationfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (300 MHz, CD₃OD, ppm) δ: 8.10 (s, 1 H), 7.80 (s, 1 H), 7.57 (d,J=7.2 Hz, 1 H), 7.16 (d, J=11.4 Hz, 1 H), 6.72 (d, J=7.2 Hz, 1 H), 6.30(d, J=10.8 Hz, 1 H), 5.17-5.25 (m, 1 H), 3.70-3.82 (m, 1 H), 2.09-2.42(m, 5 H), 1.89-2.07 (m, 2 H), 1.71-1.85 (m, 2 H), 0.99 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3 H). ¹⁹F NMR (300 MHz, CD₃OD, ppm) δ: −119.36.Mass spectrum (EI, m/z): Calculated For C₂₅H₂₅FN₄O₄, 465.2 [M+H]⁺, found465.0.

Example 164 Compound #2956-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-hydroxy-1-(isopropylsulfonyl)piperidin-3-yl)pyridin-2(1H)-one

Step 1: tert-butyl3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-hydroxypiperidine-1-carboxylate

Into a 50-mL round bottle maintained with an inert atmosphere ofnitrogen, to a solution of1-ethyl-4-fluoro-6-(6-methoxypyridin-2-yl)-1H-indazole (150 mg, 0.552mmol, 1.00 equiv.) in THF (5 mL) was added t-BuLi (1.7 N, 0.49 mL, 0.829mmol, 1.50 equiv.) with stirring at −78° C. The resulting mixture wasstirred at −78° C. for 3 h. tert-Butyl 3-oxopiperidine-1-carboxylate(165 mg, 0.829 mmol, 1.50 equiv.) was then added with stirring at −78°C. The resulting mixture was stirred at −78° C. for 2 h. The reactionwas quenched with NH₄Cl (10 mL). The resulting mixture was extractedwith EtOAc (3×10 mL). The organic layers were combined, dried overNa₂SO₄, filtered and concentrated. The residue obtained was purified bysilica gel chromatography (0-10% EtOAc/petroleum ether) to yieldtert-butyl3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-hydroxypiperidine-1-carboxylateas a white solid.

Mass spectrum (EI, m/z): Calculated For C₂₅H₃₁FN₄O₄, 471.55 [M+H], found471.8.

Step 2:3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)piperidin-3-ol

Into a 25 mL flask was added tert-butyl3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-hydroxypiperidine-1-carboxylate(168 mg, 0.357 mmol, 1.00 equiv.) in dichloromethane (1 mL) and thentrifluoroacetic acid (1 mL) at 0° C. The resulting mixture was thenwarmed to room temperature for 2 hours. The solvent was removed invacuum and the residue was carried over to next step without furtherpurification.

Mass spectrum (EI, m/z): Calculated For C₂₀H₂₃FN₄O₂, 371.43 [M+H], found371.5.

Step 3:3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-1-(isopropylsulfonyl)piperidin-3-ol

Into a 25 mL flask was added a solution of3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)piperidin-3-olTFA salt (100 mg, 0.206 mmol, 1.00 equiv) in DCM (5 mL).Propane-2-sulfonyl chloride (30 mg, 0.618 mmol, 3.00 equiv.) and Et₃N(87 μL, 0.618 mmol, 3.00 equiv.) were then added. The resulting mixturewas stirred at 20° C. for 2 h. The reaction was quenched with H₂O (10mL). The resulting mixture was extracted with DCM (3×10 mL). The organiclayers were combined, dried over Na₂SO₄, filtered and concentrated.

The residue was purified by silica gel column to yield53-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-1-(isopropylsulfonyl)piperidin-3-ol as a yellow oil.

Mass spectrum (EI, m/z): Calculated For C₂₃H₂₉FN₄O₄, 477.57 [M+H], found477.8.

Step 4:6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-hydroxy-1-(isopropylsulfonyl)piperidin-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation to yield the product as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ: 8.31 (s, 1H), 8.15 (s, 1H), 7.75 (s, 1H),7.09 (d, J=7.5 Hz, 1H), 7.02 (m, 1H), 4.52 (q, 2H), 4.05 (m, 1H), 3.81(m, 1H), 3.55 (m, 1H), 3.22 (m, 2H), 2.55 (m, 1H), 2.10 (m, 1H), 1.75(m, 1H), 1.62 (m, 1H), 1.55 (t, J=6.0 Hz, 3H), 1.40 (d, J=7.0 Hz, 6H).Mass spectrum (ESI, m/z): Calculated for C₂₂₅H₂₇FN₄O₄S, 463.54 [M+H],found: 463.7.

Example 165 Compound #2966-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-fluoro-1-(isopropylsulfonyl)piperidin-3-yl)pyridin-2(1H)-one

Into a 10 mL flask were added a solution of6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-hydroxy-1-(isopropylsulfonyl)piperidin-3-yl)pyridin-2(1H)-one(25 mg, 0.054 mmol, 1.00 equiv.) in DCM (2 mL) and then DAST (27 mg,0.162 mmol, 3.00 equiv.). The resulting mixture was stirred at −78° C.for 1 h. The reaction was quenched with MeOH (0.5 mL). The resultingmixture was extracted with DCM (3×10 mL). The organic layers werecombined, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel column to yield a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.15 (s, 1H), 8.01 (s, 1H), 7.68 (s, 1H),7.15 (d, J=7.5 Hz, 1H), 6.88 (d, J=5.6 Hz, 1H), 4.55 (q, 2H), 3.95 (m,1H), 3.75 (m, 1H), 3.18 (m, 1H), 2.92 (t, J=5.6 Hz, 1H), 2.70 (m, 1H),2.05 (m, 1H), 1.90 (m, 1H), 1.72 (m, 1H), 1.58 (t, J=6.0 Hz, 3H), 1.40(d, J=7.0 Hz, 6H).

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₆F₂N₄O₃S, 465.53 [M+H],found: 465.7.

Example 166 Compound #2976-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(1-(isopropylsulfonyl)-2,5-dihydro-1H-pyrrol-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 164 step 1 to 3 by coupling withtert-butyl-3-oxopyrrolidine-1-carboxylate, de-protection of Boc groupfollowed by demethylation to yield the product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.10 (s, 1H), 7.99 (s, 1H), 7.78 (s, 1H),7.15 (d, J=7.5 Hz, 1H), 6.85 (d, J=7.5 Hz, 1H), 5.75 (m, 1H), 4.55 (m,2H), 3.55 (m, 1H), 3.52 (m, 1H), 3.22 (m, 1H), 3.20 (m, 1 H), 3.15 (m,1H), 1.45 (t, J=7.5 Hz, 3H), 1.42 (d, J=6.5 Hz, 6H). Mass spectrum (ESI,m/z): Calculated for C₂₁H₂₃FN₄O₃S, 431.50 (M+H), found 431.7.

Example 167 Compound #2986-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(3-hydroxy-1-(isopropylsulfonyl)azetidin-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 164 step 1 to 3 by coupling with tert-butyl3-oxoazetidine-1-carboxylate, de-protection of Boc group followed bydemethylation to yield the product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.11 (s, 1H), 7.98 (s, 1H), 7.88 (d, J=6.0Hz, 1H), 7.46 (d, J=5.8 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 4.89 (m, 1H),4.65 (d, J=5.6 Hz, 1H), 4.50 (m, 2H), 3.62 (m, 2H), 3.25 (m, 1H), 1.55(t, J=6.8 Hz, 3H), 1.46 (d, J=6.0 Hz, 6H). Mass spectrum (ESI, m/z):Calculated for C₂₀H₂₃FN₄O₄S, 435.49 (M+H), found 435.6.

Example 168 Compound #2996-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-syn-7-oxo-6-oxabicyclo[3.2.1]octan-5-yl)pyridin-2(1H)-one

Step 1: ethyl3-(6-chloro-2-methoxypyridin-3-yl)-3-hydroxycyclohexane-1-carboxylate

t-BuLi (1.7 N, 9.9 mL, 16.8 mmol, 1 equiv.) was dropwise added into2-chloro-6-methoxypyridine (2 mL, 16.8 mmol, 1 equiv.) in THF (15 mL) at−78° C. for 10 min. Ethyl 3-oxocyclohexane-1-carboxylate (2.86 g, 16.8mmol, 1 equiv.) was added dropwise. The reaction was kept at −78° C. foranother 2 hour and quenched with saturated NH₄Cl, extracted with ethylacetate and purified by silica gel column using ethyl acetate/heptanesfor 10 to 50% to yield the product as a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₅H₂₀ClNO₄: 314.78 [M+H],found: 314.5.

Step 2:5-(6-chloro-2-methoxypyridin-3-yl)-6-oxabicyclo[3.2.1]octan-7-one

Ethyl3-(6-chloro-2-methoxypyridin-3-yl)-3-hydroxycyclohexane-1-carboxylate(500 mg, 1.6 mmol, 1 equiv.) and pTSA (55 mg, 0.32 mmol, 0.2 equiv.) intoluene (10 mL) was heated at 80° C. overnight. The solvent was removedand the residue was purified by silica gel column to yield the productas a residue.

Mass spectrum (ESI, m/z): Calculated for C₁₃H₁₄ClNO₃: 268.71 [M+H],found: 268.5.

Step 3:6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-syn-7-oxo-6-oxabicyclo[3.2.1]octan-5-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 1 by Suzuki coupling with1-ethyl-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazoleand demethylation to yield the product as an off-white solid.

¹H NMR (400 MHz, CDCl₃) δ: 12.7 (br, s, 1H), 8.10 (s, 1H), 7.78 (s, 1H),7.52 (d, J=6.5 Hz, 1H), 7.08 (d, J=7.0 Hz, 1H), 6.67 (d, J=6.0 Hz, 1H),4.55 (m, 2H), 2.85 (m, 1H), 2.72 (m, 2H), 2.32 (m, 2H), 2.10 (m, 2H),1.82 (m, 2H), 1.58 (t, J=6.8 Hz, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₁H₂₀FN₃O₃: 382.41 [M+H], found: 382.5.

Example 169 Compound #3004-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-6-azabicyclo[3.2.1]octan-7-one

Step 1: ethyl4-(6-chloro-2-methoxypyridin-3-yl)cyclohex-3-ene-1-carboxylate

Ethyl3-(6-chloro-2-methoxypyridin-3-yl)-3-hydroxycyclohexane-1-carboxylate(1.05 g, 3.34 mmol) in DCM (10 mL) and TFA (5 mL) mixed solvent wasstirred at room temperature for 2 hour. The solvent was removed andresidue was dried over vacuum and used in the next step without furtherpurification.

Mass spectrum (ESI, m/z): Calculated for C₁₅H₁₅ClNO₃: 296.76 [M+H],found: 296.5.

Step 2:ethyl-6-(6-chloro-2-methoxypyridin-3-yl)-7-oxabicyclo[4.1.0]heptane-3-carboxylate

Ethyl 4-(6-chloro-2-methoxypyridin-3-yl)cyclohex-3-ene-1-carboxylate(400 mg, 1.35 mmol, 1 equiv.) was treated with mCPBA (70%, 570 mg, 1.62mmol, 1.2 equiv.) in DCM (10 mL) at 0° C. for 30 min and then warmed toroom temperature. The reaction solution was partitioned between DCM andsaturated sodium bicarbonate. The organic layer was washed with brine,dried and concentrated and purified by silica gel column to yield theproduct as a residue.

Mass spectrum (ESI, m/z): Calculated for C₁₅H₁₈ClNO₄: 312.76 [M+H],found: 312.8.

Step 3:ethyl-3-azido-4-(6-chloro-2-methoxypyridin-3-yl)-4-hydroxycyclohexane-1-carboxylate

Ethyl-6-(6-chloro-2-methoxypyridin-3-yl)-7-oxabicyclo[4.1.0]heptane-3-carboxylate(200 mg, 0.642 mmol, 1 equiv.) in DMSO (2 mL) was treated with NaN₃ (208mg, 3.21 mmol, 5 equiv.) at 70° C. overnight. The reaction was cooleddown to room temperature and stirred for another 6 hour. The solutionwas partitioned between ethyl acetate and water. The organic layer wasdried, filtered and concentrated and purified by silica gel column toyield the product as an off-white solid.

Step 4:ethyl-3-amino-4-(6-chloro-2-methoxypyridin-3-yl)-4-hydroxycyclohexane-1-carboxylate

Ethyl-3-azido-4-(6-chloro-2-methoxypyridin-3-yl)-4-hydroxycyclohexane-1-carboxylate(50 mg, 0.141 mmol, 1 equiv.) was dissolved in MeOH (2 mL) and HClaqueous solution (60 μL) and treated with PtO₂ (3.2 mg, 0.014 mmol, 0.1equiv.) under 50 psi hydrogenation overnight. The catalyst was filtratedto yield the residue which was then purified by silica gel column toyield the product.

Mass spectrum (ESI, m/z): Calculated for C₁₅H₂₁ClN₂O₄: 329.79 [M+H],found: 329.5.

Step 5:4-(6-chloro-2-methoxypyridin-3-yl)-4-hydroxy-6-azabicyclo[3.2.1]octan-7-one

Ethyl-3-amino-4-(6-chloro-2-methoxypyridin-3-yl)-4-hydroxycyclohexane-1-carboxylate(30 mg, 0.09 mmol, 1 equiv.) and K₂CO₃ (12 mg, 0.09 mmol, 1 equiv.) inMeOH (2 mL) was reflux for 2 hour. The solvent was removed and theresidue was partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried, filtered, concentrated and purifiedby silica gel column to yield the product as an off-white solid.

Mass spectrum (ESI, m/z): Calculated for C₁₃H₁₅ClN₂O₃: 283.72 [M+H],found: 283.7.

Step 6:4-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-6-azabicyclo[3.2.1]octan-7-one

The title compound was prepared according to the procedure as describedin Example 1 step 1 by Suzuki coupling with1-ethyl-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazoleand demethylation to yield the product as an off-white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.18 (s, 1H), 7.96 (s, 1H), 7.52 (s, 1H),7.15 (d, J=6.6 Hz, 1H), 6.74 (d, J=6.5 Hz, 1H), 4.65 (m, 2H), 3.42 (m,1H), 3.10 (m, 1H), 2.52 (m, 1H), 2.43 (m, 1H), 1.98 (m, 2H), 1.75 (m,2H), 1.45 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₁H₂₁FN₄O₃: 397.42 [M+H], found: 397.5.

Example 170 Compound #2156-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one

Step 1:1-(tert-butyl) 2-methyl4-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate

The title compound was prepared according to the procedure as describedin Example 164 by reacting 2-chloro-6-methoxypyridine with1-(tert-butyl) 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate by t-BuLi,de-hydroxylation, reduction and then Suzuki coupling with1-ethyl-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazoleto yield the product as an off-white solid.

Mass spectrum (ESI, m/z): Calculated for C₂₆H₃₁FN₄O₅: 499.56 [M+H],found: 499.7.

Step 2: tert-butyl4-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

1-(tert-Butyl) 2-methyl4-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate(80 mg, 0.16 mmol, 1 equiv.) in THF (3 mL) at 0° C. was treated with LAH(1 M, 0.16 mL, 0.16 mmol, 1 equiv.) for 10 min. The reaction wasquenched with ice water slowly and partitioned between Rochelle saltwater and ethyl acetate. The organic layer was washed with brine, driedand purified by silica gel column to yield the product as a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₅H₃₁FN₄O₄: 471.55 [M+H],found: 477.6.

Step 3:6-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one

tert-Butyl4-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (23 mg, 0.05 mmol, 1 equiv.) and SOCl₂ (18 μL,0.244 mmol, 5 equiv.) in THF (4 mL) were refluxed overnight. Thereaction was cooled down to room temperature and quenched with saturatedsodium bicarbonate and extracted with ethyl acetate. The organic layerwas washed with brine, dried, filtered and concentrated and purified bysilica gel column to yield the product as an off-white solid.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₁FN₄O₃: 397.42 [M+H],found: 397.5.

Step 4:6-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation to yield the product as anoff-white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.18 (s, 1H), 7.75 (s, 2H), 7.10 (d, J=5.6Hz, 1H), 6.82 (d, J=6.5 Hz, 1H), 4.72 (m, 2H), 4.31 (m, 1H), 4.20 (m,1H), 3.78 (m, 2H), 2.48 (m, 2H), 1.90 (m, 2H), 1.55 (t, J=6.5 Hz, 3H).Mass spectrum (ESI, m/z): Calculated for C₂₀H₁₉FN₄O₃: 383.40 [M+H],found: 383.5.

Example 171 Compound #2056-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(2-(isopropylsulfonyl)-octahydrocyclopenta[c]pyrrol-5-yl)pyridin-2(1H)-one

Step 1: Tert-butyl5-(6-chloro-2-methoxypyridin-3-yl)-5-hydroxy-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Into a 50-mL round bottle maintained with an inert atmosphere ofnitrogen, to a solution of 2-chloro-6-methoxypyridine (200 mg, 1.390mmol, 1.00 equiv.) in THF (20 mL) was added t-BuLi (1.3 mL, 2.100 mmol,1.50 equiv) with stirring at −78° C. The resulting mixture was stirredat −78° C. for 3 h. tert-Butyl5-oxo-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (470 mg, 2.100mmol, 1.50 equiv.) was then added with stirring at −78° C. The resultingmixture was stirred at −78° C. for 2 h. The reaction was quenched withNH₄Cl (10 mL). The resulting mixture was extracted with EtOAc (3×10 mL).The organic layers were combined, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel chromatography(0-10% EtOAc/petroleum ether) to yield tert-butyl5-(6-chloro-2-methoxypyridin-3-yl)-5-hydroxy-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylateas a white solid.

Mass spectrum (ESI, m/z): Calculated for C₁₈H₂₅ClN₂O₄: 369.2[M+H],found: 368.9.

Step 2: 5-(6-chloro-2-methoxypyridin-3-yl)-octahydrocyclopenta[c]pyrrole

Into a 50-mL round bottle, to a solution of tert-butyl5-(6-chloro-2-methoxypyridin-3-yl)-5-hydroxy-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(260 mg, 0.705 mmol, 1.00 equiv.) in TFA (6 mL) was added Et₃SiH (3 mL).The resulting mixture was stirred at 90° C. overnight. After coolingdown to room temperature, the reaction was concentrated. The residue waspurified by TLC (1/10 MeOH/DCM) to yield5-(6-chloro-2-methoxypyridin-3-yl)-octahydrocyclopenta[c]pyrrole as ayellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₃H₁₇ClN₂O: 253.1 [M+H],found: 253.1.

Step 3:5-(6-chloro-2-methoxypyridin-3-yl)-2-(isopropylsulfonyl)-octahydrocyclopenta[c]pyrrole

Into a 50-mL round bottle, to a solution of5-(6-chloro-2-methoxypyridin-3-yl)-octahydrocyclopenta[c]pyrrole (100mg, 0.390 mmol, 1.00 equiv.) in DCM (10 mL) was added propane-2-sulfonylchloride (169 mg, 1.200 mmol, 3.00 equiv.), Et₃N (120 mg, 1.200 mmol,3.00 equiv.). The resulting mixture was stirred at 20° C. for 2 h. Thereaction was quenched with H₂O (100 mL). The resulting mixture wasextracted with DCM (3×10 mL). The organic layers were combined, driedover Na₂SO₄, filtered and concentrated. The residue was purified by TLC(EtOAc/petroleum ether=1/3) to yield5-(6-chloro-2-methoxypyridin-3-yl)-2-(isopropylsulfonyl)-octahydrocyclopenta[c]pyrroleas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₆H₂₃ClN₂O₃S: 359.1[M+H],found: 359.1.

Step 4:6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(2-(isopropylsulfonyl)-octahydrocyclopenta[c]pyrrol-5-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation to yield the product as a yellowsolid.

¹H NMR (400 MHz, CD₃OD) δ: 8.14 (s, 1H), 7.79 (s, 1H), 7.60 (d, J=7.2Hz, 1H), 7.19 (d, J=10.6 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 4.53-4.58 (m,2H), 3.33-3.39 (m, 5H), 3.174-3.22 (m, 1H), 2.85 (brs, 2H), 2.38-2.43(m, 2H), 1.50-1.59 (m, 5H), 1.38-1.48 (m, 6H). ¹⁹F NMR (400 MHz, CD₃OD)δ: −77.68, −119.22. Mass spectrum (ESI, m/z): Calculated forC_(24.5)H_(29.25)F_(1.75)N₄O_(3.5)S, 473.2[M−0.25CF₃COOH+H], found:473.2.

Example 172 Compound #2046-(1-ethyl-4-fluoroindazol-6-yl)-3-[3-(propane-2-sulfonyl)-3-azaspiro[5.5]undecan-9-yl]-1H-pyridin-2-one

The title compound was prepared according to the procedure as describedin Example 171 by coupling and demethylation to yield the product as anoff-white solid.

¹H NMR (400 MHz, CD₃OD) δ 8.17 (s, 1H), 7.78 (s, 1H), 7.55 (d, J=7.2 Hz,1H), 7.17 (d, J=11.2 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 4.53-4.57 (m, 2H),3.33-3.38 (m, 4H), 2.80-2.84 (m, 1H), 1.81-1.92 (m, 2H), 1.68-1.75 (m,4H), 1.40-1.65 (m, 8H), 1.22-1.37 (m, 8H). ¹⁹F NMR (400 MHz, CD₃OD) δ−77.58, −119.22. Mass spectrum (ESI, m/z): Calculated forC_(28.46)H_(35.73)F_(3.19)N₄O_(4.46)S, 515.2[M−0.73CF₃COOH+H], found:515.2.

Example 173 Compound #2095-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-N-isopropyl-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

Step 1:1-ethyl-4-fluoro-6-(6-methoxy-5-(octahydrocyclopenta[c]pyrrol-5-yl)pyridin-2-yl)-1H-indazole

The title compound was prepared according to the procedure as describedin Example 157 by coupling and deprotection to yield the product as anbrown oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₅FN₄O: 381.2 [M+H], found:381.2.

Step 2:5-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxyypyridin-3-yl)-N-isopropyl-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

Into a 50-mL round bottle, to a solution of1-ethyl-4-fluoro-6-(6-methoxy-5-(octahydrocyclopenta[c]pyrrol-5-yl)pyridin-2-yl)-1H-indazole(150 mg, 0.390 mmol, 1.00 equiv.) in DCM (10 mL) was added2-isocyanatopropane (100 mg, 1.180 mmol, 3.00 equiv.), TEA (119 mg,1.180 mmol, 3.00 equiv.). The resulting mixture was stirred at 20° C.overnight. The mixture was concentrated under vacuum. The residue waspurified by silica gel with ethyl acetate/petroleum ether (50:50). Thecollected fractions were combined and concentrated under vacuum to yield5-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-N-isopropyl-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamideas a white solid.

Mass spectrum (ESI, m/z): Calculated for C₂₆H₃₂FN₅O₂: 466.3[M+H], found:466.3.

Step 3:5-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-N-isopropyl-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation to yield the product as a whitesolid.

¹H NMR (300 MHz, CD₃OD) δ 8.15 (s, 1H), 7.79 (s, 1H), 7.60 (d, J=7.5 Hz,1H), 7.17-7.21 (m, 1H), 6.74 (d, J=7.5 Hz, 1H), 4.52-4.57 (m, 2H),3.85-3.92(m, 1H), 3.33-3.49 (m, 5H), 2.84-2.87 (m, 2H), 2.36-2.38(m,2H), 1.52-1.57(m, 5H), 1.17-1.19 (m, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ−77.49, −119.22. Mass spectrum (ESI, m/z): Calculated forC_(25.8)H_(30.4)F_(2.2)N₅O_(2.8): 452.2[M−0.4CF₃COOH+H], found: 452.2.

Example 174 Compound #2015-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-N-isopropyl-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

Step 1:6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(octahydrocyclopenta[c]pyrrol-5-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation to yield the product as a whitesolid.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₃FN₄O: 367.2 [M+H], found:367.1.

Step 2:5-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-N-isopropyl-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

Into a 50-mL round-bottom, a mixture of dimethylcyanocarbonimidodithioate (11 mg, 0.082 mmol, 1.00 equiv.) andisopropylamine (5 mg, 0.082 mmol, 1.00 equiv.) in acetonitrile (5 mL)was heated under reflux for 5 hours. After cooling the solution,6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(octahydrocyclopenta[c]pyrrol-5-yl)pyridin-2(1H)-one(30 mg, 0.082 mmol, 1.00 equiv.) and 3 N sodium hydroxide solution(0.027 mL, 0.820 mmol, 1.00 equiv.) were added. The mixture was stirredfor 5 minutes and a solution of silver nitrate (14 mg, 0.082 mmol, 1.00equiv.) in acetonitrile (0.5 mL) was added dropwise. The reactionmixture was stirred at 0° C. for 2 hours and at room temperature for 2hours. The reaction mixture was filtered and the residue washed withacetonitrile. The solvent was evaporated and the residue was purified byPrep-HPLC with the following conditions (16#-Waters 2767-5): Column,SunFire Prep C18,19*100 mm, 5 um; mobile phase, Water with 0.05% TFA andCH₃CN (50% CH₃CN up to 65% in 15 min, up to 100% in 0.1 min); Detector,UV 220 & 254 nm. The resulting solution was concentrated under vacuum toyield(Z)—N′-cyano-5-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-N-isopropyl-hexahydrocyclopenta[c]pyrrole-2(1H)-carboximidamideas off-white solid.

¹H NMR (300 MHz, CD₃OD) δ 8.09 (s, 1H), 7.73 (s, 1H), 7.56 (d, J=7.2 Hz,1H), 7.13 (d, J=12.0 Hz, 1H), 6.69 (d, J=7.2 Hz, 1H), 4.47-4.49 (m, 2H),4.15-4.24 (m, 1H), 3.51-3.68 (m, 4H), 3.33-3.34 (m, 1H), 2.83-2.84 (m,2H), 2.27-2.36 (m, 2H), 1.51-1.57 (m, 2H), 1.46-1.48 (m, 3H), 1.17-1.29(m, 6H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −77.15, −119.19. Mass spectrum(ESI, m/z): Calculated for C_(26.68)H_(30.34)F_(2.02)N₇O_(1.68):476.2[M−0.34CF₃COOH+H], found: 476.2.

Example 175 Compound #2038-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-1,3-diazaspiro[4.5]decane-2,4-dione

Step 1:8-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol

2-Methoxy-6-(naphthalen-2-yl)pyridine (500 mg, 2.13 mmol, 1 equiv) inTHF (10 mL) was treated dropwise with t-BuLi (1.7 N, 1.32 mL, 2.23 mmol,1.05 equiv.) at −78° C. for 30 min. Then 1,4-dioxaspiro[4.5]decan-8-one(332 mg, 2.13 mmol, 1 equiv.) in THF (5 mL) was dropwise added into thereaction. The reaction was stirred for another 2 hour at −78° C. andthen warmed to room temperature. The reaction was quenched withsaturated ammonium chloride and extracted with ethyl acetate. Theorganic layer was washed with brine, dried and concentrated and purifiedby silica gel column using 20-80% ethyl acetate in heptanes to yield thetitle compound as a colorless oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₅NO₄: 391.47 [M+H], found:391.2.

Step 2: 4-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)cyclohexan-1-one

8-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol(150 mg, 0.4 mmol, 1 equiv.) in mixed solvent of acetone andconcentrated HCl (0.2 mL) in THF (7 mL) was stirred at room temperatureovernight. The solvent was removed and the residue was partitionedbetween ethyl acetate and saturated sodium bicarbonate. The organiclayer was washed with brine and dried and concentrated to yield aresidue which was then filled into a PARR shaker with 5% Pd/C (100 mg)under 50 psi hydrogenation at room temperature for 4 hours. The catalystwas filtered and the residue was concentrated and purified by silica gelcolumn using 5-20% ethyl acetate in heptanes to yield the title productas a colorless oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₁NO₂: 332.42 [M+H], found:332.6.

Step 3:8-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-1,3-diazaspiro[4.5]decane-2,4-dione

The title compound was prepared according to the procedure as describedin Example 60 by reacting4-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)cyclohexan-1-one with(NH₄)₂CO₃ and NH₄OH and KCN followed by demethylation to yield theproduct as a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.15 (s, 1H), 7.95 (m, 2H), 7.75 (m, 1H),7.58 (m, 2H), 7.43 (m, 1H), 7.30 (m, 1H), 6.92 (m, 1H), 2.65 (m, 1H),2.10 (m, 2H), 1.82 (m, 2H), 1.52 (m, 2H), 1.32 (m, 2H). Mass spectrum(ESI, m/z): Calculated for C₂₃H₂₁N₃O₃, 388.44 (M+H), found 388.7.

Example 176 Compound #1917-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-1,3-diazaspiro[4.5]decane-2,4-dione

The title compound was prepared according to the procedure as describedin Example 175 by coupling, de-hydroxylation and reacting6-(naphthalen-2-yl)-3-(3-oxocyclohexyl)pyridin-2(1H)-one with (NH₄)₂CO₃and NH₄OH and KCN followed by demethylation to yield the product as awhite solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.11 (s, 1H), 7.85 (m, 2H), 7.65 (m, 1H),7.50 (m, 2H), 7.38 (m, 1H), 7.26 (m, 1H), 6.75 (m, 1H), 2.98 (m, 1H),2.16 (m, 2H), 2.01 (m, 2H), 1.81 (m, 2H), 1.62 (m, 2H). Mass spectrum(ESI, m/z): Calculated for C₂₃H₂₁N₃O₃, 388.44 (M+H), found 388.6.

Example 177 Compound #185 and #2011-cyano-3-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)cyclohexylcarbamate and1-hydroxy-3-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)cyclohexane-1-carboxamide

TMSCN (26 μL, 0.198 mmol, 1.3 equiv) was added dropwise to a stirringsolution of 6-(naphthalen-2-yl)-3-(3-oxocyclohexyl)pyridin-2(1H)-one (50mg, 0.151 mmol, 1 equiv.) and ZnI₂ (2 mg, 0.004 mmol, 0.023 equiv.) inDCM (4.8 mL) at 23° C. The resulting dark amber solution was stirred at23° C. for 1 hour. The resulting mixture was then diluted with DCM (20mL) shake with saturated aq NaHCO₃ (10 mL). The organic layer wascollected and dried with MgSO₄, filter, concentrated to yield a clearorange oil, which was then purified by silica gel column using 20-80%ethyl acetate in heptanes to yield

1-cyano-3-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)cyclohexylcarbamate as a white solid (15 mg, 26%). Mass spectrum (ESI, m/z):Calculated for C₂₃H₂₁N₃O₃: 388.44 [M+H], found: 388.6.

and1-hydroxy-3-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)cyclohexane-1-carboxamideas a white solid (28 mg, 50%). ¹H NMR (400 MHz, CD₃OD) δ: 8.10 (s, 1H),7.95 (m, 2H), 7.69 (m, 1H), 7.58 (m, 2H), 7.45 (m, 1H), 7.32 (m, 1H),6.68 (m, 1H), 3.25 (m, 1H), 2.32 (m, 2H), 1.82 (m, 3H), 1.53 (m, 3H).Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂N₂O₃: 363.43 [M+H],found: 363.6.

Example 178 Compound #189 and #188Syn-7-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-1-oxa-3-azaspiro[4.5]decane-2,4-dioneandanti-7-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-1-oxa-3-azaspiro[4.5]decane-2,4-dione

The title compounds were prepared according to the procedure asdescribed in Example 4 step 6-9 by reacting6-(naphthalen-2-yl)-3-(3-oxocyclohexyl)pyridin-2(1H)-one withTMSCN/AlCl₃, hydrolysis and esterification, coupling with2,2,2-trichloroacetyl isocyanate and base catalyzed cyclization followedby demethylation to yield

Syn-7-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-1-oxa-3-azaspiro[4.5]decane-2,4-dioneas an off white solid. ¹H NMR (400 MHz, d₆-DMSO) δ: 11.5 (br, s, 1H),8.35 (s, 1H), 7.99 (m, 3H), 7.85 (d, J=6.0 Hz, 1H), 7.55 (m, 2H), 7.44(d, J=6.0 Hz, 1H), 6.70 (d, J=4.5 Hz, 1H), 4.10 (m, 1H), 2.05 (m, 2H),1.95 (m, 2H), 1.84 (m, 2H), 1.50 (m, 2H). Mass spectrum (ESI, m/z):Calculated for C₂₃H₂₀N₂O₄: 389.42 [M+H], found: 389.5.

andAnti-7-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-1-oxa-3-azaspiro[4.5]decane-2,4-dioneas an off-white solid. ¹H NMR (400 MHz, d₆-DMSO) δ: 11.8 (br, s, 1H),8.45 (s, 1H), 8.02 (m, 2H), 7.98 (m, 1H), 7.88 (d, J=6.5 Hz, 1H), 7.62(m, 2H), 7.45 (d, J=6.0 Hz, 1H), 6.72 (d, J=4.5 Hz, 1H), 4.05 (m, 1H),2.18 (m, 2H), 1.98˜1.82 (m, 4H), 1.35 (m, 2H). Mass spectrum (ESI, m/z):Calculated for C₂₃H₂₀N₂O₄: 389.42 [M+H], found: 389.6.

Example 179 Compound #1926-(naphthalen-2-yl)-3-(tetrahydro-2H-pyran-4-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 164 by coupling with tetrahydro-4H-pyran-4-one, Et₃SiHreduction and demethylation to yield the product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.15 (s, 1H), 8.01 (d, J=6.5 Hz, 1H), 7.95(m, 3H), 7.70 (d, J=6.0 Hz, 1H), 7.58 (d, J=6.0 Hz, 1H), 7.52 (d, J=6.0Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 4.10 (m, 2H), 3.62 (m, 2H), 3.15 (m,1H), 1.82 (m, 4H). Mass spectrum (ESI, m/z): Calculated for C₂₀H₁₉NO₂,306.38 (M+H), found 306.5.

Example 180 Compound #1946-(naphthalen-2-yl)-3-(piperidin-4-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 164 by coupling with tert-butyl4-oxopiperidine-1-carboxylate, Et₃SiH reduction and demethylation toyield the product as a white solid.

Mass spectrum (ESI, m/z): Calculated for C₂₀H₂₀N₂O, 305.39 (M+H), found305.2.

Example 181 Compound #1863-(1-(methylsulfonyl)piperidin-4-yl)-6-(naphthalen-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 164 step 3 by coupling6-(naphthalen-2-yl)-3-(piperidin-4-yl)pyridin-2(1H)-one with MsClfollowed by demethylation to yield the product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.20 (s, 1H), 8.02 (s, 1H), 7.90 (d, J=7.2Hz, 1H), 7.75 (d, J=7.0 Hz, 1H), 7.58 (m, 2H), 7.45 (m, 1H), 7.12 (m,1H), 6.75 (d, J=6.0 Hz, 1H), 3.35 (m, 2H), 3.10 (m, 1H), 3.02 (s, 3H),2.98 (m, 2H), 2.10 (m, 2H), 1.82 (m, 2H). Mass spectrum (ESI, m/z):Calculated for C₂₁H₂₂N₂O₃S, 383.48 (M+H), found 383.7.

Example 182 Compound #1903-(1-(ethylsulfonyl)piperidin-4-yl)-6-(naphthalen-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 164 step 3 by coupling6-(naphthalen-2-yl)-3-(piperidin-4-yl)pyridin-2(1H)-one with EtSO₂Clfollowed by demethylation to yield the product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.24 (s, 1H), 7.98 (s, 1H), 7.92 (d, J=5.2Hz, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.60 (m, 2H), 7.48 (m, 1H), 6.72 (d,J=6.5 Hz, 1H), 3.95 (m, 2H), 3.35 (m, 2H), 3.10 (m, 1H), 2.98 (m, 2H),2.10 (m, 2H), 1.82 (m, 2H), 1.25 (t, J=7.5 Hz, 3H). Mass spectrum (ESI,m/z): Calculated for C₂₃H₂₆N₂O₃S, 397.51 [M+H], found: 397.6.

Example 183 Compound #2003-(1-(isopropylsulfonyl)piperidin-4-yl)-6-(naphthalen-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 164 step 3 by coupling6-(naphthalen-2-yl)-3-(piperidin-4-yl)pyridin-2(1H)-one with i-PrSO₂Clfollowed by demethylation to yield the product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.25 (s, 1H), 8.01 (s, 1H), 7.95 (d, J=5.2Hz, 1H), 7.72 (d, J=6.5 Hz, 1H), 7.62 (m, 2H), 7.50 (m, 1H), 6.75 (d,J=5.5 Hz, 1H), 3.98 (m, 2H), 3.20 (m, 2H), 3.12 (m, 1H), 2.98 (m, 2H),2.02 (m, 2H), 1.67 (m, 2H), 1.38 (d, J=6.5 Hz, 6H). Mass spectrum (ESI,m/z): Calculated for C₂₃H₂₆N₂O₃S, 411.53 [M+H], found: 411.7.

Example 184 Compound #1996-(6-fluoronaphthalen-2-yl)-3-(1-(isopropylsulfonyl)piperidin-4-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 164 step 3 by coupling6-(6-fluoronaphthalen-2-yl)-3-(piperidin-4-yl)pyridin-2(1H)-one withi-PrSO₂Cl followed by demethylation to yield the product as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ: 8.21 (s, 1H), 8.02 (s, 1H), 7.95 (d, J=6.2Hz, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.45 (m, 1H), 7.30 (m, 1H), 6.98 (m,1H), 6.72 (m, 1H), 3.98 (m, 2H), 3.55 (m, 2H), 3.10 (m, 4H), 2.10 (m,1H), 1.95 (m, 1H), 1.70 (m, 1H), 1.35 (d, J=7.5 Hz, 6H). Mass spectrum(ESI, m/z): Calculated for C₂₃H₂₅FN₂O₃S, 429.52 [M+H], found: 429.7.

Example 185 Compound #1986-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(1-(isopropylsulfonyl)piperidin-4-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 164 step 3 by coupling6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(piperidin-4-yl)pyridin-2(1H)-onewith i-PrSO₂Cl followed by demethylation to yield the product as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ: 8.15 (s, 1H), 8.01 (s, 1H), 7.68 (s, 1H),7.15 (d, J=7.5 Hz, 1H), 6.88 (d, J=5.6 Hz, 1H), 4.76 (m, 2H), 4.15 (m,2H), 3.31 (m, 1H), 3.05 (m, 1H), 2.21 (m, 1H), 1.98 (m, 1H), 1.76 (m,1H), 1.60 (m, 1H), 1.45 (m, 6H). Mass spectrum (ESI, m/z): Calculatedfor C₂₂H₂₇FN₄O₃S, 447.54 [M+H], found: 447.7.

Example 186 Compound #2136-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(1-(isopropylsulfonyl)pyrrolidin-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 164 step 3 by coupling6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(pyrrolidin-3-yl)pyridin-2(1H)-onewith i-PrSO₂Cl followed by demethylation to yield the product as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ: 12.8 (br, s, 1H), 8.18 (s, 1H), 7.98 (s, 1H),7.75 (s, 1H), 7.18 (d, J=6.5 Hz, 1H), 6.92 (d, J=7.6 Hz, 1H), 4.52 (m,2H), 3.65 (m, 1H), 3.52 (m, 1H), 3.42 (m, 1H), 3.23 (m, 1H), 2.28 (m,1H), 2.12 (m, 1H), 1.55 (t, J=7.0 Hz, 3H), 1.38 (d, J=6.5 Hz, 6H). Massspectrum (ESI, m/z): Calculated for C₂₁H₂₅FN₄O₃S, 433.51 [M+H], found:433.8.

Example 187 Compound #2116-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(1-(isopropylsulfonyl)piperidin-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 164 step 3 by coupling6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(piperidin-3-yl)pyridin-2(1H)-onewith i-PrSO₂Cl followed by demethylation to yield the product as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ: 8.12 (s, 1H), 7.99 (s, 1H), 7.72 (s, 1H),7.18 (d, J=6.5 Hz, 1H), 6.92 (d, J=6.6 Hz, 1H), 4.52 (m, 2H), 3.95 (m,1H), 3.80 (m, 1H), 3.25 (m, 1H), 3.15 (m, 2H), 3.02 (m, 2H), 2.05 (m,1H), 1.88 (m, 1H), 1.80 (m, 1H), 1.62 (t, J=6.5 Hz, 3H), 1.40 (d, J=7.5Hz, 6H). Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₇FN₄O₃S, 447.54[M+H], found: 447.4.

Example 188 Compound #2146-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(1-(isopropylsulfonyl)azetidin-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 164 step 3 by coupling3-(azetidin-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-onewith i-PrSO₂Cl followed by demethylation to yield the product as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ: 8.05 (s, 1H), 7.96 (s, 1H), 7.69 (d, J=6.0Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.31 (s, 1H), 4.72 (t, J=9.5 Hz, 1H),4.48 (m, 1H), 4.45 (m, 2H), 3.78 (m, 1H), 3.45 (m, 2H), 3.15 (m, 1H),1.56 (t, J=7.8 Hz, 3H), 1.42 (d, J=6.5 Hz, 6H). Mass spectrum (ESI,m/z): Calculated for C₂₀H₂₃FN₄O₂S, 419.49 (M+H), found 419.6.

Example 189 Compound #2066-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(8-(isopropylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 164 step 3 by coupling3-(8-azabicyclo[3.2.1]octan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-onewith i-PrSO₂Cl followed by demethylation to yield the product as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ: 8.12 (s, 1H), 7.72 (s, 2H), 7.08 (d, J=7.0Hz, 1H), 6.82 (d, J=4.0 Hz, 1H), 4.56 (q, J=6.1 Hz, 2H), 4.30 (m, 2H),3.22 (m, 2H), 2.48 (m, 2H), 2.18 (m, 2H), 1.95 (m, 2H), 1.72 (m, 2H),1.55 (t, J=7.0 Hz, 3H), 1.45 (m, 6H). Mass spectrum (ESI, m/z):Calculated for C₂₄H₂₉FN₄O₃S, 473.58 (M+H), found 473.7.

Example 190 Compound #2083-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-N-isopropyl-8-azabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared according to the procedure as describedin Example 164 step 3 by coupling3-(8-azabicyclo[3.2.1]octan-3-yl)-6-(1-ethyl-4-fluoro-1H-indazol-6-yl)pyridin-2(1H)-onewith 2-isocyanatopropane followed by demethylation to yield the productas a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.10 (s, 1H), 7.72 (s, 1H), 7.65 (s, 1H),7.08 (d, J=6.0 Hz, 1H), 6.82 (d, J=7.0 Hz, 1H), 4.55 (m, 2H), 4.32 (m,2H), 4.08 (m, 1H), 2.95 (m, 1H), 2.56 (m, 2H), 2.15 (m, 2H), 1.85 (m,4H), 1.65 (t, J=7.5 Hz, 3H), 1.38 (m, 6H). Mass spectrum (ESI, m/z):Calculated for C₂₅H₃₀FN₅O₂, 452.55 (M+H), found 452.7.

Example 191 Compound #1976-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(1-(2-hydroxyacetyl)piperidin-4-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 164 step 3 by coupling6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-3-(piperidin-4-yl)pyridin-2(1H)-onewith 2-hydroxyacetyl chloride followed by demethylation to yield theproduct as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.15 (s, 1H), 7.52 (s, 1H), 7.22 (m, 1H),7.10 (m, 1H), 6.75 (d, J=6.5 Hz, 1H), 4.52 (agq, J=11.5 Hz, 2H), 4.48(q, J=6.7 Hz, 2H), 3.95 (m, 4H), 3.42 (m, 2H), 3.10 (m, 1H), 3.05 (m,2H), 1.45 (t, J=8.5 Hz, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₁H₂₃FN₄O₃, 399.44 (M+H), found 399.6.

Example 192 Compound #1956-(naphthalen-2-yl)-3-(4,5,6,7-tetrahydro-2H-indazol-5-yl)pyridin-2(1H)-one

Step 1:2-((dimethylamino)methylene)-4-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)cyclohexan-1-one

6-(Naphthalen-2-yl)-3-(4-oxocyclohexyl)pyridin-2(1H)-one (150 mg, 0.453mmol, 1 equiv.) in 1,1-dimethoxy-N,N-dimethylmethanamine (4 mL) washeated to 100° C. overnight. The reaction was partitioned between ethylacetate and water. The organic layer was dried and concentrated andpurified by silica gel column using 30% ethyl acetate in heptanes toyield the product as a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₅H₂₆N₂O₂, 387.50 [M+H],found: 387.4.

Step 2:5-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-4,5,6,7-tetrahydro-2H-indazole

2-((Dimethylamino)methylene)-4-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)cyclohexan-1-one(25 mg, 0.07 mmol, 1 equiv.) and hydrazine (5 mg, 0.14 mmol, 2 equiv.)in EtOH (2 mL) were heated to reflux for 4 hour. The solvent was removedand the residue was purified by silica gel column to yield the productas a colorless oil.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₁N₃O, 355.44 [M+H], found:355.4.

Step 3:6-(naphthalen-2-yl)-3-(4,5,6,7-tetrahydro-2H-indazol-5-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 1 step 5 by demethylation of5-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-4,5,6,7-tetrahydro-2H-indazolewith TMSCl/NaI to yield the product as a white solid.

¹H NMR (400 MHz, d₆-DMSO) δ: 7.35 (s, 1H), 7.20 (s, 1H), 7.15 (d, J=5.0Hz, 1H), 7.05 (d, J=6.5 Hz, 1H), 6.90 (m, 2H), 6.73 (m, 2H), 6.65 (m,1H), 5.98 (m, 1H), 2.35 (m, 2H), 2.28 (m, 2H), 2.10 (m, 1H), 1.73 (m, 1H). Mass spectrum (ESI, m/z): Calculated for C₂₂H₁₉N₃O, 342.41 [M+H],found: 342.4.

Example 193 Compound #1876-(naphthalen-2-yl)-3-(4,5,6,7-tetrahydrobenzo[d]isoxazol-5-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure as describedin Example 193 by reacting2-((dimethylamino)methylene)-4-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)cyclohexan-1-one with hydroxylamine followed by demethylation withTMSCl/NaI to yield the product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.14 (s, 1H), 8.02 (s, 1H), 7.95 (d, J=5.2Hz, 1H), 7.86 (s, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.55 (m, 2H), 7.42 (m,1H), 6.65 (d, J=7.5 Hz, 1H), 3.30 (m, 1H), 3.20 (m, 1H), 2.65 (m, 1H),2.46 (m, 1H), 2.40 (m, 1H), 1.73 (m, 1H), 1.48 (m, 1H). Mass spectrum(ESI, m/z): Calculated for C₂₂H₁₈N₂O₂, 343.14 [M+H], found: 343.3.

Example 194 Compound #1969-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-azaspiro[5.5]undecan-1-one

Step 1: ethyl4-(6-chloro-2-methoxypyridin-3-yl)cyclohex-3-ene-1-carboxylate

The title compound was prepared according to the procedure described inExample 175 by coupling of 2-chloro-6-methoxypyridine with ethyl4-oxocyclohexane-1-carboxylate by t-BuLi, de-hydroxylation with HCl toyield the product as a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₅H₁₈ClNO₃, 295.76 (M+H),found 295.4.

Step 2: ethyl4-(6-chloro-2-methoxypyridin-3-yl)-1-(2-cyanoethyl)cyclohex-3-ene-1-carboxylate

To a solution of DIPEA (95 μL, 0.672 mmol, 1.4 equiv.) in THF (5 mL) wasadded dropwise n-BuLi (2.5 N, 270 μL, 0.672 mmol, 1.4 equiv.) at −78° C.for 10 min. Ethyl4-(6-chloro-2-methoxypyridin-3-yl)cyclohex-3-ene-1-carboxylate (143 mg,0.48 mmol, 1 equiv.) in THF (1 mL) was added into the reaction at −78°C. The reaction was stirred for another 2 hour at −78° C.3-Bromopropanenitrile (100 μL, 0.768 mmol, 1.6 equiv.) was added intothe reaction dropwise. The reaction was then warmed to room temperatureover 2 hour. The solvent was removed and residue was partitioned betweenethyl acetate and water. The organic layer was dried and concentratedand purified by silica gel column to yield the product as a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₈H₂₁ClN₂O₃, 349.83 (M+H),found 349.4.

Step 3: 9-(6-chloro-2-methoxypyridin-3-yl)-2-azaspiro[5.5]undecan-1-one

Ethyl4-(6-chloro-2-methoxypyridin-3-yl)-1-(2-cyanoethyl)cyclohex-3-ene-1-carboxylate(150 mg, 0.43 mmol, 1 equiv.) and K₂CO₃ (297 mg, 2.15 mmol, 5 equiv.) inMeOH (7.5 mL) were refluxed overnight. The solvent was removed and theresidue was dissolved in MeOH (10 mL) and HCl concentrated aqueoussolution (0.75 mL) and treated with PtO₂ (10 mg, 0.043 mmol, 0.1 equiv.)under 50 psi hydrogenation overnight. The catalyst was filtrated and theresidue was purified by silica gel column using 1:1 heptanes/ethylacetate to yield the product as a colorless oil.

Mass spectrum (ESI, m/z): Calculated for C₁₆H₂₁ClN₂O₂, 308.81 (M+H),found 308.9.

Step 4:9-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-2-azaspiro[5.5]undecan-1-one

The title compound was prepared according to the procedure described inExample 1 step 1 by Suzuki coupling9-(6-chloro-2-methoxypyridin-3-yl)-2-azaspiro[5.5]undecan-1-one with1-ethyl-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazoleto yield the product as a white solid.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₉FN₄O₂, 437.53 (M+H),found 437.7.

Step 5:9-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-azaspiro[5.5]undecan-1-one

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product asa white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.10 (s, 1H), 7.79 (d, J=6.0 Hz, 1H), 7.75(s, 1H), 7.05 (d, J=7.5 hz, 1H), 6.95 (d, J=4.2 Hz, 1H), 6.32 (br, s,1H), 4.52 (q, J=5.5 Hz, 2H), 3.31 (br, s, 2H), 2.98 (m, 1H), 2.10 (m,4H), 1.85 (m, 2H), 1.80 (m, 2H), 1.72 (m, 2H), 1.55 (m, 3H), 1.40 (m,2H). Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₇FN₄O₂, 423.50 (M+H),found 423.3.

Example 195 Compound #2078-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-azaspiro[4.5]decan-1-one

The title compound was prepared according to the procedure as describedin Example 194 step 1-5 by reacting ethyl4-(6-chloro-2-methoxypyridin-3-yl)cyclohex-3-ene-1-carboxylate with2-bromoacetonitrile followed by cyclization, Suzuki coupling anddemethylation to yield the product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.10 (s, 1H), 7.78 (m, 1H), 7.72 (s, 1H),7.06 (d, J=7.5 Hz, 1H), 6.89 (d, J=5.5 Hz, 1H), 5.72 (s, br, 1H), 4.52(q, J=6.2 Hz, 2H), 3.38 (m, 2H), 3.01 (m, 1H), 2.25 (m, 2H), 2.02 (m,4H), 1.82 (m, 2H), 1.45 (t, J=6.8 Hz, 3H), 1.40 (m, 2H). Mass spectrum(ESI, m/z): Calculated for C₂₃H₂₅FN₄O₂, 408.48 (M+H), found 408.7.

Example 196 Compound #2823-(3-methyl-1,1-dioxido-1,2,5-thiadiazolidin-3-yl)-6-(naphthalen-2-yl)pyridin-2(1H)-one

Step 1:2-amino-2-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]propanenitrile

Into a 40-mL vial, were placed a solution of1-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]ethan-1-one (1 g, 3.60mmol, 1.00 equiv.) in NH₃ (in methanol) (30 mL), TMSCN (560 mg, 5.60mmol, 1.57 equiv.), NH₄Cl (380 mg, 7.20 mmol, 1.97 equiv.). Theresulting solution was stirred for 2 days at 25° C. The resultingmixture was concentrated under vacuum. The resulting solution wasdiluted with of EA. The solids were filtered out. The resulting mixturewas concentrated under vacuum to yield2-amino-2-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]propanenitrile as ayellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₉H₁₇N₃O, 287.1 (M+H−NH₂),found 287.1.

Step 2: 2-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]propane-1,2-diamine

Into a 100-mL round-bottom flask, were placed a solution of2-amino-2-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]propanenitrile (1g, 3.30 mmol, 1.00 equiv.) in ether (30 mL), LAH (250 mg, 6.59 mmol,2.00 equiv.). The resulting solution was stirred for 1 h at 25° C. Thereaction was then quenched by the addition of sodium sulfate.10H₂O. Thesolids were filtered out. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column withdichloromethane/methanol (1:1) to yield2-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]propane-1,2-diamine as ayellow oil.

Mass spectrum (ESI, m/z): Calculated for C₁₉H₂₁N₃O, 308.2 (M+H), found308.1.

Step 3:3-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-3-methyl-1,2,5-thiadiazolidine1,1-dioxide

Into a 50-mL round-bottom flask, were placed a solution of2-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]propane-1,2-diamine (50 mg,0.16 mmol, 1.00 equiv.) in pyridine (10 mL), sulfamoylamine (31 mg, 0.32mmol, 1.98 equiv.). The resulting solution was stirred for 16 h at 115°C. in an oil bath. The resulting mixture was concentrated under vacuum.The resulting solution was extracted with ethyl acetate (3×50 mL) andthe organic layers combined. The resulting mixture was washed with 3×50mL of sodium chloride (aq). The resulting mixture was concentrated undervacuum. The residue (40 mg) was purified by Prep-HPLC with the followingconditions (1#waters2767-5): Column, SunFire Prep C18,19*150 mm 5 umHPrepC-001(T)18600256819513816414 04; mobile phase, Phase A:water with0.05% TFA Phase B:CH₃CN (15% CH₃CN up to 80% in 10 min, up to 100% CH₃CNin 0.1 min, hold 100% in 1.9 min, down to 15% CH₃CN in 0.1 min, hold 15%in 1.9 min); Detector, UV220&254 nm, to yield3-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-3-methyl-1,2,5-thiadiazolidine1,1-dioxide as a light yellow solid.

¹H NMR (400 MHz, DMSO) δ: 8.66 (s, 1H), 8.28 (d, J=8.8 Hz, 1H),7.94-8.05 (m, 4H), 7.78 (d, J=7.6 Hz, 1H), 7.53-7.58 (m, 3H), 7.08 (brm,1H), 4.10 (s, 3H), 3.92 (d, J=12.4 Hz, 1H), 3.76 (d, J=9.6 Hz, 1H), 1.60(s, 3H).

Mass spectrum (ESI, m/z): Calculated for C₁₉H₁₉N₃O₃S, 370.1 (M+H), found370.0.

Step 4:3-(3-methyl-1,1-dioxido-1,2,5-thiadiazolidin-3-yl)-6-(naphthalen-2-yl)pyridin-2(1H)-one

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, were placed a solution of3-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-3-methyl-1-[6],2,5-thiadiazolidine-1,1-dione(120 mg, 0.32 mmol, 1.00 equiv.) in dichloromethane (15 mL). Theresulting solution was stirred at −78° C. in a dry ice bath. BBr₃(121mg, 0.49 mmol, 1.50 equiv.) was then added dropwise. The resultingsolution was stirred for 5 h at 25° C. The reaction was then quenched bythe addition of methanol. The resulting mixture was concentrated undervacuum. The residue (100 mg) was purified by Prep-HPLC with thefollowing conditions (1#waters2767-5): Column, SunFire Prep C18,19*150mm 5 umH PrepC-001(T)18600256819513816414 04; mobile phase, PhaseA:water with 0.05% TFA; Phase B:CH₃CN (15% CH₃CN up to 80% in 10 min, upto 100% CH₃CN in 0.1 min, hold 100% in 1.9 min, down to 15% CH₃CN in 0.1min, hold 15% in 1.9 min); Detector, UV220&254 nm to yield3-(3-methyl-1,1-dioxido-1,2,5-thiadiazolidin-3-yl)-6-(naphthalen-2-yl)pyridin-2(1H)-oneas a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ: 12.00 (bs, 1H), 8.36 (s, 1H), 7.95-8.02 (m,3H), 7.78-7.86 (m, 2H), 7.57-7.61 (m, 2H), 7.41 (s, 1H), 7.06 (t, J=7.6Hz, 1H), 6.79 (d, J=6.8 Hz, 1H), 3.91-3.96 (m, 1H), 3.23-3.33 (m, 1H),1.61 (s, 3H).

Mass spectrum (ESI, m/z): Calculated for C₁₈H₁₇N₃O₃S, 356.1 (M+H), found356.0.

Example 197 Compound #283N-[4-methyl-4-[6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl]imidazolidin-2-ylidene]amino]carbonitrile

Step 1:(E/Z)-4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methylimidazolidin-2-ylidene]amino]carbonitrile

Into a 50-mL round-bottom flask, were placed a solution of2-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]propane-1,2-diamine (50 mg,0.16 mmol, 1.00 equiv.) in ethanol (10 mL),[bis(methylsulfanyl)methylidene](cyano)amine (36 mg, 0.25 mmol, 1.51equiv.), potassium hydroxide (18 mg, 0.32 mmol, 1.97 equiv.). Theresulting solution was stirred for 16 h at 80° C. in an oil bath. Thereaction mixture was cooled. The resulting mixture was concentratedunder vacuum. The residue (40 mg) was purified by Prep-HPLC with thefollowing conditions (1#waters2767-5): Column, SunFire Prep C18,19*150mm 5 umH PrepC-001(T)18600256819513816414 04; mobile phase, PhaseA:water with 0.05% TFA Phase B:CH₃CN (20% CH₃CN up to 80% in 10 min, upto 100% CH₃CN in 0.1 min, hold 100% in 1.9 min, down to 20% CH₃CN in 0.1min, hold 20% in 1.9 min); Detector, UV220&254 nm to yield[[(2Z)-4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methylimidazolidin-2-ylidene]amino]carbonitrileas a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.66 (s, 1H), 8.59 (s, 1H), 8.28 (d, J=8.4Hz, 1H), 7.94-8.05 (m, 4H), 7.76-7.81 (m, 2H), 7.54-7.57 (m, 2H), 4.08(s, 3H), 3.73 (d, J=10.0 Hz, 1H), 3.61 (d, J=10.0 Hz, 1H), 1.58 (s, 3H).Mass spectrum (ESI, m/z): Calculated for C₂₁H₁₉N₅O, 358.2 (M+H), found358.1.

Step 2:(E/Z)—N-[4-methyl-4-[6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl]imidazolidin-2-ylidene]amino]carbonitrile

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation of(E/Z)-4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methylimidazolidin-2-ylidene]amino]carbonitrilewith TMSCl/NaI to yield the product as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.44 (s, 1H), 8.36 (s, 1H), 7.96-8.02 (m,3H), 7.81-7.88 (m, 2H), 7.58-7.60 (m, 2H), 7.52 (d, J=6.8 Hz, 1H), 6.77(br, m, 1H), 3.64-3.69 (m, 2H), 1.57 (s, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₀OH₁₇N₅O, 344.1 (M+H), found 344.1.

Example 198 Compound #285[E]-3-[-2-(hydroxyimino)-4-methylimidazolidin-4-yl]-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-one

Step 1:4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methylimidazolidine-2-thione

Into a 100-mL round-bottom flask, were placed a solution of2-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]propane-1,2-diamine (700mg, 2.28 mmol, 1.00 equiv.) in ethanol/H₂O (30/5 mL). CS₂ (6 mL),triethylamine (2 mL) was added. The resulting solution was stirred for 3h at 70° C. in an oil bath. The reaction progress was monitored byTLC/LCMS (ethyl acetate/petroleum ether=1:1). The reaction mixture wascooled with a water bath. The resulting mixture was concentrated undervacuum. The resulting solution was extracted with ethyl acetate (3×30mL) and the organic layers combined and dried over anhydrous sodiumsulfate. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:4) to yield4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methylimidazolidine-2-thioneas a yellow solid.

Mass spectrum (ESI, m/z): calcd for C₂₀H₁₉N₃OS, found 350.1 [M+H]⁺

Step 2:2-methoxy-3-[5-methyl-2-(methylsulfanyl)-4,5-dihydro-1H-imidazol-5-yl]-6-(naphthalen-2-yl)pyridine

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed a solution of4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methylimidazolidine-2-thione(450 mg, 1.29 mmol, 1.00 equiv.) in methanol (20 mL). iodomethane (264mg, 1.86 mmol, 1.50 equiv.) was added. The resulting solution wasstirred for 1.5 h at 70° C. in an oil bath. The reaction progress wasmonitored by TLC (ethyl acetate/petroleum ether=1:1). The reactionmixture was cooled with a water bath. The resulting mixture wasconcentrated under vacuum. The resulting solution was extracted withethyl acetate (3×30 mL) and the organic layers combined and dried overanhydrous sodium sulfate. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:5), to yield2-methoxy-3-[5-methyl-2-(methylsulfanyl)-4,5-dihydro-1H-imidazol-5-yl]-6-(naphthalen-2-yl)pyridineas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₁N₃OS, found 364.1 [M+H]⁺.

Step 3:(E)-N-methoxy-4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methylimidazolidin-2-imineand(2Z)—N-methoxy-4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methylimidazolidin-2-imine

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed2-methoxy-3-[5-methyl-2-(methylsulfanyl)-4,5-dihydro-1H-imidazol-5-yl]-6-(naphthalen-2-yl)pyridine(50 mg, 0.14 mmol, 1.00 equiv.), O-methylhydroxylamine hydrochloride(347 mg, 4.15 mmol, 30.00 equiv.), potassium carbonate (193 mg, 1.40mmol, 10.00 equiv.), 4 Å molecular sieves (2 g), tetrahydrofuran (20mL). The resulting solution was stirred overnight at 120° C. in an oilbath. The reaction progress was monitored by TLC/LCMS (ethylacetate/petroleum ether=1:1). The reaction was then quenched by theaddition of water (10 mL). The resulting solution was extracted withethyl acetate (2×30 mL) and the organic layers combined and concentratedunder vacuum to yield(2E/Z)—N-methoxy-4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methylimidazolidin-2-imineas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₁N₃OS, found 364.2.[M+H]⁺.

Step 4:[E]-3-[2-(hydroxyimino)-4-methylimidazolidin-4-yl]-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-oneand3-[(2Z)-2-(hydroxyimino)-4-methylimidazolidin-4-yl]-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-one

Into a 8-mL vial purged and maintained with an inert atmosphere ofnitrogen, were placed a solution of NaI (9 mg, 1.00 equiv.) inacetonitrile (1 mL), TMSCl (10.2 mg, 0.09 mmol, 1.50 equiv.) was added.N-[(2E)-4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methylimidazolidin-2-ylidene]hydroxylamine(22.9 mg, 0.07 mmol, 1.00 equiv.). The resulting solution was stirredfor 1 h at room temperature. The reaction progress was monitored byTLC/LCMS (dichloromethane/methanol=5:1). The reaction was then quenchedby the addition of water (0.3 mL). The solids were filtered out. Theresidue (4 mL) was purified by Prep-HPLC with the following conditions(1#-Waters 2767-5): Column, SunFire Prep C18, 5 um, 19*100 mm; mobilephase, Water of 0.05% NH₄HCO₃ and CH₃CN (20% CH₃CN up to 90% in 10 min;Detector, UV 220&254 nm to yield3-[(2E)-2-(hydroxyimino)-4-methylimidazolidin-4-yl]-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-one as a yellow solid.

¹H NMR (300 MHz, Methanol-d₄, ppm): δ 8.22 (s, 1H), 8.00 (m, 3H), 7.77(d, J=7.4 Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 6.79(d, J=7.4 Hz, 1H), 3.96 (m, 2H), 3.82 (s, 3H), 1.78 (s, 3H). Massspectrum (ESI, m/z): Calculated for C₂₁H₂₁N₃OS, found 349.2 M+H]⁺ and2.4 mg (11%) of3-[(2Z)-2-(hydroxyimino)-4-methylimidazolidin-4-yl]-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-oneas a light yellow solid. ¹H NMR (400 MHz, CD₃OD) δ: 8.21 (s, 1H),7.97-8.21 (m, 2H), 7.90-7.94 (m, 1H), 7.75-7.77 (m, 1H), 7.71 (d, J=7.2Hz, 1H), 7.55-7.59 (m, 2H), 6.76 (d, J=7.2 Hz, 1H), 3.61-3.68 (m, 5H),1.66 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₁N₃OS, 349.2(M+H), found 349.2.

Example 199 Compound #2864-[2-hydroxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methylimidazolidine-2-thione

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation of4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methylimidazolidine-2-thionewith TMSCl/NaI to yield the product as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ: 8.75 (s, 1H), 8.37 (s, 1H), 8.18 (s, 1H),7.95-8.03 (m, 3H), 7.85 (d, J=7.4 Hz, 1H), 7.52-7.60 (m, 3H), 7.17 (bs,1H), 6.79 (bs, 1H), 3.65-3.67 (m, 2H), 1.55 (s, 3H). Mass spectrum (ESI,m/z): Calculated for C₂₁H₂₁N₃OS, 336.1 (M+H), found 336.0.

Example 200 Compound #2873-(2-amino-4-methyl-4,5-dihydro-1H-imidazol-4-yl)-6-(naphthalen-2-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 198 by displacement of2-methoxy-3-[5-methyl-2-(methylsulfanyl)-4,5-dihydro-1H-imidazol-5-yl]-6-(naphthalen-2-yl)pyridinewith ammonium hydroxide followed by demethylation with TMSCl/NaI toyield the product as a light yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ: 8.36 (s, 1H), 7.95-8.03 (m, 3H), 7.85 (d,J=8.4 Hz, 1H), 7.50-7.60 (m, 3H), 6.80 (d, J=6.9 Hz, 1H), 3.79 (d,J=10.5 Hz, 1H), 3.70 (d, J=10.2 Hz, 1H), 1.61 (s, 3H). Mass spectrum(ESI, m/z): Calculated for C₁₉H₁₈N₄O, 319.2 (M+H), found 319.1.

Example 201 Compound #1673-[6-methyl-5H,6H,7H-imidazo[2,1-c][1,2,4]triazol-6-yl]-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-one

Step 1:3-[(2Z)-2-hydrazinylidene-4-methylimidazolidin-4-yl]-2-methoxy-6-(naphthalen-2-yl)pyridine

Into a 50-mL round-bottom flask, were placed a solution of2-methoxy-3-[4-methyl-2-(methylsulfanyl)-4,5-dihydro-1H-imidazol-4-yl]-6-(naphthalen-2-yl)pyridine(250 mg, 0.69 mmol, 1.00 equiv.) in methanol (10 mL), hydrazine hydrate(31 mg, 0.68 mmol, 0.99 equiv.). The resulting solution was stirred for16 h at 80° C. in an oil bath. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withdichloromethane/methanol (10:1) to yield3-[(2Z)-2-hydrazinylidene-4-methylimidazolidin-4-yl]-2-methoxy-6-(naphthalen-2-yl)pyridineas a yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₀H₂₁N₅O, 348.2 (M+H), found348.1.

Step 2:2-methoxy-3-[6-methyl-5H,6H,7H-imidazo[2,1-c][1,2,4]triazol-6-yl]-6-(naphthalen-2-yl)pyridine

Into a 50-mL round-bottom flask, were placed a solution of3-[(2Z)-2-hydrazinylidene-4-methylimidazolidin-4-yl]-2-methoxy-6-(naphthalen-2-yl)pyridine(240 mg, 0.69 mmol, 1.00 equiv.) in N,N-dimethylformamide (10 mL),(diethoxymethoxy)ethane (153 mg, 1.03 mmol, 1.49 equiv.). The resultingsolution was stirred for 16 h at 75° C. in an oil bath. The resultingmixture was concentrated under vacuum. The residue (150 mg) was purifiedby Flash-Prep-HPLC with the following conditions (CombiFlash-1): Column,C18 silica gel; mobile phase, water (0.05% NH₄HCO₃) and CH₃CN=35%increasing to water (0.05% NH₄HCO₃) and CH₃CN=75% within 30 min;Detector, UV 254 nm to yield2-methoxy-3-[6-methyl-5H,6H,7H-imidazo[2,1-c][1,2,4]triazol-6-yl]-6-(naphthalen-2-yl)pyridineas a yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₁₉N₅O, 358.2 (M+H), found358.2.

Step 3:3-[6-methyl-5H,6H,7H-imidazo[2,1-c][1,2,4]triazol-6-yl]-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-one

The title compound was prepared according to the procedure described inExample step 51 by demethylation with TMSCl/NaI to yield the product aslight yellow oil.

¹H NMR (400 MHz, DMSO-d₆) δ: 9.15 (bs, 1H), 8.56 (s, 1H), 8.37 (s, 1H),7.97-8.04 (m, 3H), 7.84-7.86 (m, 1H), 7.59-7.67 (m, 3H), 6.82 (bs, 1H),4.38-4.45 (m, 2H), 1.79 (s, 3H). Mass spectrum (ESI, m/z): Calculatedfor C₂₀H₁₇N₅O, 344.1 (M+H), found 344.1.

Example 202 Compound #2223-(4-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl)-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-one

Step 1: 2-amino-2-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]propanamide

Into a 50-mL round-bottom flask, were placed a solution of2-amino-2-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]propanenitrile (500mg, 1.65 mmol, 1.00 equiv.) in methanol (20 mL), sodium hydroxide (99mg, 2.48 mmol, 1.50 equiv.), H₂O₂ (30%) (374 mg, 11.00 mmol, 6.67equiv.). The resulting solution was stirred for 1 h at 25° C. Theresulting solution was extracted with ethyl acetate (3×100 mL) and theorganic layers combined. The resulting mixture was washed with sodiumchloride (aq) (3×50 mL). The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column withdichloromethane/methanol (20:1) to yield2-amino-2-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]propanamide as alight yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₁₉H₁₉N₃O₂, 322.1 (M+H), found322.1.

Step 2:4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methyl-4,5-dihydro-1H-imidazol-5-one

Into a 50-mL round-bottom flask, were placed a solution of2-amino-2-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]propanamide (100mg, 0.31 mmol, 1.00 equiv.) in toluene (10 mL), (diethoxymethoxy)ethane(69 mg, 0.47 mmol, 1.50 equiv.), AcOH (2 mg, 0.03 mmol, 0.11 equiv.).The resulting solution was stirred for 16 h at 60° C. in an oil bath.The resulting mixture was concentrated under vacuum. Water was added.The resulting solution was extracted with ethyl acetate (3×50 mL) andthe organic layers combined. The resulting mixture was washed withsodium chloride (aq) (3×50 mL). The mixture was dried over anhydroussodium sulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum to yield4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methyl-4,5-dihydro-1H-imidazol-5-oneas a yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₀H₁₇N₃O₂, 332.1 (M+H), found332.1.

Step 3:3-(4-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl)-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-one

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product asa light yellow solid.

¹H NMR (400 MHz, CD₃OD) δ: 9.46 (s, 1H), 8.27 (s, 1H), 7.95-8.07 (m,4H), 7.77-7.80 (m, 1H), 7.59-7.64 (m, 2H), 6.91 (d, J=7.6 Hz, 1H), 1.96(s, 3H).

Mass spectrum (ESI, m/z): Calculated for C₁₉H₁₅N₃O₂, 318.1 (M+H), found318.1.

Example 203 Compound #2233-(2,4-dimethyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl)-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-one

The title compound was prepared according to the procedure described inExample 202 by condensation followed by demethylation with TMSCl/NaI toyield the product as a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.26 (s, 1H), 8.01-8.05 (m, 3H), 7.95-7.97(m, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.59-7.64 (m, 2H), 6.90 (d, J=7.6 Hz,1H), 2.54 (s, 3H), 1.86 (s, 3H). Mass spectrum (ESI, m/z): Calculatedfor C₂₀H₁₇N₃O₂, 332.1 (M+H), found 332.0.

Example 204 Compound #2883-[(2E)-2-(hydroxyimino)-4-methylimidazolidin-4-yl]-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-one

The title compound was prepared according to the procedure described inExample 198 by displacement of2-methoxy-3-[5-methyl-2-(methylsulfanyl)-4,5-dihydro-1H-imidazol-5-yl]-6-(naphthalen-2-yl)pyridinewith hydroxylamine followed by demethylation with TMSCl/NaI to yield theproduct as an off-white solid.

¹H NMR (400 MHz, Methanol-d₄) δ: 8.25 (s, 1H), 8.02-8.04 (m, 2H),7.94-8.00 (m, 1H), 7.77-7.79 (m, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.59-7.62(m, 2H), 6.81 (d, J=7.6 Hz, 1H), 3.91-4.01 (m, 2H), 1.79 (s, 3H). Massspectrum (ESI, m/z): Calculated for C₂₀H₁₉N₃OS, 335.1, found 335.2,[M+H]⁺

Example 205 Compound #2893-[2-(dimethylamino)-4-methyl-4,5-dihydro-1H-imidazol-4-yl]-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-one

The title compound was prepared according to the procedure described inExample 198 by displacement of2-methoxy-3-[5-methyl-2-(methylsulfanyl)-4,5-dihydro-1H-imidazol-5-yl]-6-(naphthalen-2-yl)pyridinewith dimethylamine HCl salt followed by demethylation with TMSCl/NaI toyield the product as a light yellow solid.

¹H NMR (300 MHz, Methanol-d₄, ppm) δ: 8.12 (s, 1H), 7.82-7.92 (m, 3H),7.61-7.68 (m, 2H), 7.47-7.50 (m, 2H), 6.70 (d, J=7.5 Hz, 1H),3.78-3.87(m, 2H), 3.03(s, 6H), 1.68 (s, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₀H₁₉N₃OS, 347.2 (M+H), found 347.2.

Example 206 Compound #290N-[4-methyl-4-[6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl]-4,5-dihydro-1H-imidazol-2-yl]methanesulfonamide

The title compound was prepared according to the procedure described inExample 198 by displacement of2-methoxy-3-[5-methyl-2-(methylsulfanyl)-4,5-dihydro-1H-imidazol-5-yl]-6-(naphthalen-2-yl)pyridinewith ammonium hydroxide followed by demethylation with TMSCl/NaI toyield the product as a white solid.

¹H NMR (300 MHz, Methanol-d₄, ppm) δ: 8.19 (s, 1H), 7.94-7.98 (m, 2H),7.88-7.91 (m, 1H), 7.72-7.75 (m, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.52-7.57(m, 2H), 6.75 (d, J=7.2 Hz, 1H), 3.75-3.84 (m, 2H), 2.92 (s, 3H), 1.69(s, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₀H₁₉N₃OS, 397.1(M+H), found 397.0.

Example 207 Compound #152 3-[5-methyl-6-oxo-5H, 6H,7H-imidazo[2,1-c][1,2,4]triazol-5-yl]-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-one

Step 1:3-benzyl-5-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-5-methyl-2-sulfanylideneimidazolidin-4-one

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed2-amino-2-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]propanenitrile (2g, 6.59 mmol, 1.00 equiv.), N,N-dimethylformamide (30 m L),(isothiocyanatomethyl)benzene (1.475 g, 9.89 mmol, 1.50 equiv.). Theresulting solution was stirred overnight at room temperature. Thereaction was then quenched by the addition of water (3 mL). The reactionprogress was monitored by TLC/LCMS (ethyl acetate/petroleum ether=1:1).The resulting solution was extracted with ethyl acetate and the organiclayers combined and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:3). Theproduct was dissolved in DMF, hydrogen chloride (2M) (3 mL) was added.The resulting solution was stirred for 6 h at 100° C. in an oil bath.The reaction progress was monitored by TLC/LCMS (ethyl acetate/petroleumether=1:1). The resulting solution was extracted with ethyl acetate andthe organic layers combined and concentrated under vacuum. The mixturewas dried over anhydrous sodium sulfate. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:5) to yield3-benzyl-5-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-5-methyl-2-sulfanylideneimidazolidin-4-oneas a yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₇H₂₃N₃O₂S, 454.2 (M+H), found454.1.

Step 2:1-benzyl-4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methyl-2-(methylsulfanyl)-4,5-dihydro-1H-imidazol-5-one

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed3-benzyl-5-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-5-methyl-2-sulfanylideneimidazolidin-4-one(485 mg, 1.02 mmol, 1.00 equiv., 95%), methanol (20 mL), iodomethane(0.4 mL, 2.00 equiv.), sodium hydroxide (44 mg, 1.10 mmol, 1.00 equiv.).The resulting solution was stirred for 2 h at 40° C. in an oil bath. Thereaction progress was monitored by TLC (ethyl acetate/petroleumether=1:1). The resulting mixture was concentrated under vacuum. Theresidue was dissolved in of ethyl acetate. The solids were filtered out.The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(5:1) to yield 1-benzyl-4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methyl-2-(methylsulfanyl)-4, 5-dihydro-1H-imidazol-5-oneas a yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₈H₂₅N₃O₄S, 468.2 [M+H]⁺,found 468.1.

Step 3: N-1-benzyl-4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methyl-5-oxo-4,5-dihydro-1H-imidazol-2-yl]carbohydrazide

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed1-benzyl-4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methyl-2-(methylsulfanyl)-4,5-dihydro-1H-imidazol-5-one(424 mg, 0.9 mmol, 1.00 equiv.), methanol (10 mL), formohydrazide (540mg, 9 mmol, 10.00 equiv.). The resulting solution was stirred overnightat 70° C. in an oil bath. The reaction progress was monitored byTLC/LCMS (ethyl acetate/petroleum ether=1:1). The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:5) to yieldN-1-benzyl-4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methyl-5-oxo-4,5-dihydro-1H-imidazol-2-yl]carbohydrazideas a white solid.

Mass spectrum (ESI, m/z): Calculated for C₂₈H₂₅N₅O₃, 480.2, [M+H]⁺,found 480.1.

Step 4:7-benzyl-5-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-5-methyl-5H,6H,7H-imidazo[2,1-c][1,2,4]triazol-6-one

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placedN-[1-benzyl-4-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-4-methyl-5-oxo-4,5-dihydro-1H-imidazol-2-yl]carbohydrazide(272 mg, 0.57 mmol, 1.00 equiv.), acetaldehyde (10 mL). The resultingsolution was stirred overnight at 120° C. in an oil bath. The reactionprogress was monitored by TLC/LCMS (dichloromethane/methanol=20:1). Theresulting mixture was concentrated under vacuum. The reaction was thenquenched by the addition of water (10 mL). The resulting solution wasextracted with of ethyl acetate and the organic layers combined. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:2) to yield7-benzyl-5-[2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl]-5-methyl-5H,6H,7H-imidazo[2,1-c][1,2,4]triazol-6-oneas a yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₈H₂₃N₅O₂, 462.2, [M+H]⁺,found 462.3.

Step 5:3-[7-benzyl-5-methyl-6-oxo-5H,6H,7H-imidazo[2,1-c][1,2,4]triazol-5-yl]-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-one

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product asa yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₇H₂₁N₅O₂, 448.2, [M+H]⁺,found 448.1.

Step 6: 3-[5-methyl-6-oxo-5H, 6H,7H-imidazo[2,1-c][1,2,4]triazol-5-yl]-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-one

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed3-[7-benzyl-5-methyl-6-oxo-5H,6H,7H-imidazo[2,1-c][1,2,4]triazol-5-yl]-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-one(40 mg, 0.09 mmol, 1.00 equiv.), toluene (5 mL), trichloroaluminum (70mg, 0.52 mmol, 6.00 equiv.), amine hydrochloride (28.6 mg, 0.53 mmol,6.00 equiv.). The resulting solution was stirred for 4 h at 60° C. in anoil bath. The reaction progress was monitored by TLC/LCMS(dichloromethane/methanol=10:1). The reaction was then quenched by theaddition of water (1 mL). The resulting solution was extracted with ofethyl acetate and the organic layers combined and concentrated undervacuum. The residue (60 mg) dissolved in DMF was purified by Prep-HPLCwith the following conditions (1#-Waters 2767-5): Column, SunFire PrepC18, 5 um, 19*100 mm; mobile phase, Water of 0.05% TFA and CH₃CN (20%CH₃CN up to 90% in 10 min, up to 100% in 2 min, down to 20% in 2 min;Detector, UV 220&254 nm to yield3-[5-methyl-6-oxo-5H,6H,7H-imidazo[2,1-c][1,2,4]triazol-5-yl]-6-(naphthalen-2-yl)-1,2-dihydropyridin-2-oneas a white solid.

¹H NMR (400 MHz, CD₃OD, ppm) δ: 8.44 (s, 1H), 8.25 (s, 1H), 8.10 (d,J=7.6 Hz, 1H), 8.00-8.04 (m, 2H), 7.94-7.96 (m, 1H), 7.78 (d, J=8.4 Hz,1H), 7.59-7.61 (m, 2H), 6.88 (d, J=7.2 Hz, 1H), 2.01 (s, 3H). Massspectrum (ESI, m/z): Calculated for C₂₀H₁₅N₅O₂, 358.1, [M−H]⁺, found358.0.

Example 208 Compound #1533-methyl-3-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-1H-imidazo[1,2-a]imidazol-2(3H)-one

Step1:2-((1,3-dioxolan-2-yl)methylamino)-1-benzyl-4-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-4-methyl-1H-imidazol-5(4H)-one

Into 50 ml round-bottom flask,3-benzyl-5-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-5-methyl-2-thioxoimidazolidin-4-one(500 mg, 1.102 mmol, 1.00 equiv.) was dissolved in methanol, and then(1,3-dioxolan-2-yl)methanamine (227 mg, 2.201 mmol, 2.00 equiv.) andEt₃N (557 mg, 5.504 mmol, 5.00 equiv.) was added. The mixture wasstirred at ambient temperature and t-BuOOH (497 mg, 5.515 mmol, 5.00equiv.) was added dropwise. The reaction mixture was stirred for 16 h at25° C. The mixture was quenched by ice-water and extracted with ethylacetate. The organic layers combined and concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1/1) to yield2-((1,3-dioxolan-2-yl)methylamino)-1-benzyl-4-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-4-methyl-1H-imidazol-5(4H)-oneas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₃₁H₃₀N₄O₄, 523.2 [M+H]⁺, found523.3.

Step 2:1-benzyl-3-(2-hydroxy-6-(naphthalen-2-yl)pyridin-3-yl)-3-methyl-1H-imidazo[1,2-a]imidazol-2(3H)-one

Into 50 ml round-bottom flask,2-((1,3-dioxolan-2-yl)methylamino)-1-benzyl-4-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-4-methyl-1H-imidazol-5(4H)-one(200 mg, 1.191 mmol, 1.00 equiv.) was dissolved in 1,2-dichloroethane,and then TFA was added. The reaction mixture was stirred for 16 h at100° C. The pH value of the solution was adjusted to 6 with NaHCO₃ (aq)and extracted with ethyl acetate. The organic layers combined andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with DCM/MeOH (20/1) to yield1-benzyl-3-(2-hydroxy-6-(naphthalen-2-yl)pyridin-3-yl)-3-methyl-1H-imidazo[1,2-a]imidazol-2(3H)-oneas light yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₈H₂₂N₄O₂, 447.2 (M+H), found447.1.

Step 3:3-methyl-3-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-1H-imidazo[1,2-a]imidazol-2(3H)-one

The title compound was prepared according to the procedure described inExample 207 step 6 by de-benzylation to yield the product as anoff-white solid.

¹H NMR (400 MHz, CD₃OD, ppm) δ: 8.25 (s, 1H), 8.16 (d, J=7.6 Hz, 1H),8.00-8.05 (m, 2H), 7.95-7.97 (m, 1H), 7.77-7.79 (m, 1H), 7.59-7.64 (m,2H), 7.27 (d, J=2.0 Hz, 1H), 7.23(d, J=2.4 Hz, 1H), 6.92(d, J=7.6 Hz,1H), 1.86 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₁H₁₆N₄O₂,357.1 [M+H]⁺, found 357.1.

Example 209 Compound #291N-(4-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-isopropyl-4,5-dihydro-1H-imidazol-2-yl)cyanamide

Step 1:5-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropylimidazolidine-2,4-dione

Into 100 ml seal tube,1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-one(2.0 g, 6.185 mmol, 1.0 eq.) was dissolved in ethanol (15 mL),trimethylsilanecarbonitrile (0.92 g, 9.274 mmol, 1.5 eq.), ammoniumhydroxide (2 mL) and (NH₄)₂CO₃ (1.12 g, 11.656 mmol, 2 eq.) was added.The mixture was stirred for 24 h at 100° C. The mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withPE/EA (2/1) to yield5-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropylimidazolidine-2,4-dioneas a yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₀FN₃O₃, 394.1 [M+H]⁺,found 394.1.

Step 2:4-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-isopropylimidazolidin-2-one

Into 100 ml round-bottom flask,5-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropylimidazolidine-2,4-dione(1.2 g, 3.050 mmol, 1.0 eq.) was dissolved in THF, LAH (0.58 g, 15.282mmol, 5.0 eq.) was added. The mixture was stirred for 16 h at 80° C. Themixture was quenched by Na₂SO₄.10H₂O and filtered out. The organic layerwas concentrated under vacuum. The residue was applied onto a silica gelcolumn with DCM/MeOH (10/1) to yield4-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-isopropylimidazolidin-2-oneas yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂FN₃O₂, 380.2 [M+H]⁺,found 380.2.

Step 3:4-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-isopropylimidazolidine-2-thione

Into 100 ml round-bottom flask,4-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-isopropylimidazolidin-2-one(500 mg, 1.318 mmol, 1.0 eq.) was dissolved in toluene (30 mL),Lawesson's Reagent (2.66 g, 6.577 mmol, 5.0 eq.) was added. The mixturewas stirred for 16 h at 100° C. The mixture was concentrated undervacuum. The residue was applied onto a silica gel column with PE/EA(1/1) to yield4-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-isopropylimidazolidine-2-thioneas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂FN₃OS, 396.1 [M+H]⁺,found 396.3.

Step 4:6-(8-fluoronaphthalen-2-yl)-3-(5-isopropyl-2-(methylthio)-4,5-dihydro-1H-imidazol-5-yl)-2-methoxypyridine

Into 40 ml vial,4-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-isopropylimidazolidine-2-thione(250 mg, 0.632 mmol, 1.0 eq.) was dissolved in methanol (5 mL) andiodomethane (48 mg, 0.338 mmol, 2.0 eq.) was added. The mixture wasstirred for 2 h at 70° C. The mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with DCM/MeOH (10/1) toyield6-(8-fluoronaphthalen-2-yl)-3-(5-isopropyl-2-(methylthio)-4,5-dihydro-1H-imidazol-5-yl)-2-methoxypyridineas light yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₄FN₃OS, 410.2 [M+H]⁺,found 410.3.

Step 5:N-(4-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-isopropyl-4,5-dihydro-1H-imidazol-2-yl)cyanamide

Into a 40-mL vial, were placed6-(8-fluoronaphthalen-2-yl)-3-(4-isopropyl-2-(methylthio)-4,5-dihydro-1H-imidazol-4-yl)-2-methoxypyridine(300 mg, 0.733 mmol, 1.00 equiv.), cyanamide (154 mg, 3.663 mmol, 5.0equiv.), N-ethyl-N-isopropylpropan-2-amine (189 mg, 1.462 mmol, 2.0equiv.). The resulting solution was stirred overnight at 90° C. Themixture was concentrated under vacuum. The residue was applied onto asilica gel column with DCM/MeOH (10/1) to yieldN-(4-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-isopropyl-4,5-dihydro-1H-imidazol-2-yl)cyanamideas a yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₂FN₅O, 404.2 [M+H]⁺, found404.4.

Step 6:N-(4-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-isopropyl-4,5-dihydro-1H-imidazol-2-yl)cyanamide

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product asa light yellow solid.

¹H NMR (400 MHz, CD₃OD, ppm) δ: 8.55 (s, 1H), 8.45 (s, 1H), 8.10 (d,J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.65 (d,J=7.2 Hz, 1H), 7.56-7.61 (m, 1H), 7.30-7.34 (m, 2H), 6.86 (d, J=7.2 Hz,1H), 4.21 (d, J=11.6 Hz, 1H), 4.14 (d, J=12.0 Hz, 1H), 2.71-2.76 (m,1H), 1.03 (d, J=7.2 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H). ¹⁹F NMR (400 MHz,CD₃OD, ppm) δ: −77.04,−124.44. Mass spectrum (ESI, m/z): Calculated ForC₂₂H₂₀FN₅O, 389/43 [M+H]⁺, found 390.2.

Example 210 Compound #1565-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropyl-5H-imidazo[2,1-c][1,2,4]triazol-6(7H)-one

Step1:3-benzyl-5-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropylimidazolidine-2,4-dione

Into a 100-mL round-bottom flask, were placed5-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropylimidazolidine-2,4-dione(1 g, 2.542 mmol, 1.00 equiv.), (bromomethyl)benzene (522 mg, 3.052mmol, 1.20 equiv.), K₂CO₃(527 mg, 3.813 mmol, 1.50 equiv.), DMF (10 mL).The resulting solution was stirred for 4 h at 25° C. The reactionprogress was monitored by PE:EA=3:1. The reaction was then quenched bythe addition of water (30 mL). The resulting solution was extracted withethyl acetate (3×50 mL) and the organic layers combined. The resultingmixture was washed with brine (1×50 mL). The mixture was dried overanhydrous sodium sulfate. The solids were filtered out. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:3) to yield3-benzyl-5-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropylimidazolidine-2,4-dioneas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₁NO₃, 484.2 (M+H), found484.4.

Step 2:1-benzyl-4-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-isopropyl-2-(methylthio)-1H-imidazol-5(4H)-one

The title compound was prepared according to the procedure described inExample 209 step 3-4 by treatment with Lawesson's agent followed byreacting with MeI to yield the title compounds as a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₃₀H₂₈FN₃O₂S, 514.2 (M+H),found 514.4.

Step 3:N′-(1-benzyl-4-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-isopropyl-5-oxo-4,5-dihydro-1H-imidazol-2-yl)formohydrazide

Into a 50-mL round-bottom flask, were placed1-benzyl-4-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-isopropyl-2-(methylthio)-1H-imidazol-5(4H)-one(80 mg, 0.156 mmol, 1.00 equiv.), MeOH (5 mL), formohydrazide (47 mg,0.783 mmol, 5.00 equiv.). The resulting solution was stirred forovernight at 80° C. The reaction progress was monitored by LCMS. Theresulting mixture was concentrated under vacuum. The residue was appliedonto TLC with ethyl acetate/petroleum ether (1:1) to yieldN′-(1-benzyl-4-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-isopropyl-5-oxo-4,5-dihydro-1H-imidazol-2-yl)formohydrazideas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₃₀H₂₈FN₅O₃, 526.2 (M+H), found526.4.

Step 4:7-benzyl-5-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropyl-5H-imidazo[2,1-c][1,2,4]triazol-6(7H)-one

Into a 50-mL round-bottom flask, were placedN′-(1-benzyl-4-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-4-isopropyl-5-oxo-4,5-dihydro-1H-imidazol-2-yl)formohydrazide(100 mg, 0.190 mmol, 1.00 equiv.), AcOH (5 mL). The resulting solutionwas stirred for overnight at 100° C. The reaction progress was monitoredby LCMS. The resulting mixture was concentrated under vacuum. Theresidue was applied onto TLC with ethyl acetate/petroleum ether (1:1) toyield7-benzyl-5-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropyl-5H-imidazo[2,1-c][1,2,4]triazol-6(7H)-oneas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₃₀H₂₆FN₅O₂, 508.2 (M+H), found508.1.

Step 5:5-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropyl-5H-imidazo[2,1-c][1,2,4]triazol-6(7H)-one

The title compound was prepared according to the procedure described inExample 207 by de-benzylation followed by demethylation with TMSCl/NaIto yield the product as a colorless oil.

¹H NMR (300 MHz, CD₃OD) δ: 8.57 (s, 1H), 8.40 (s, 1H), 7.98-8.06 (m,2H), 7.81-7.84 (m, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.50-7.57 (m, 1H),7.24-7.30 (m, 1H), 6.81 (d, J=7.8 Hz, 1H), 1.22-1.33 (m, 1H), 1.02 (d,J=6.9 Hz, 3H), 0.92 (d, J=6.9 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ:−77.18, −124.30. Mass spectrum (ESI, m/z): Calculated forC_(29.78)H_(21.89)F_(12.67)N₅O_(9.78), 404.1 (M−3.89CF₃COOH+H), found404.2.

Example 211 Compound #292(Z)-6-(8-fluoronaphthalen-2-yl)-3-(4-isopropyl-2-(methoxyimino)imidazolidin-4-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 198 by displacement with methoxyamine followed by demethylationwith TMSCl/NaI to yield the product as a white solid.

¹H NMR (400 MHz, CD₃OD, ppm) δ: 8.43 (s, 1H), 8.08 (d, J=8.4 Hz, 1H),7.88 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H),7.54-7.59 (m, 1H), 7.28-7.33 (m, 1H), 6.82 (d, J=7.2 Hz, 1H), 3.92 (d,J=10.4 Hz, 1H), 3.73 (d, J=10.0 Hz, 1H), 3.65 (s, 3H), 2.70-2.79 (m,1H), 1.04 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.8 Hz, 3H). ¹⁹F NMR (300 MHz,CD₃OD, ppm) δ: −124.47. Mass spectrum (ESI, m/z): Calculated forC₂₂H₂₃FN₄O₂, 395.2 [M+H]⁺, found 395.2.

Example 212 Compound #293(E)-6-(8-fluoronaphthalen-2-yl)-3-(4-isopropyl-2-(methoxyimino)imidazolidin-4-yl)-5-methylpyridin-2(1H)-one

Step 1:5-(5-bromo-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropylimidazolidine-2,4-dione

Into 50 ml round-bottom flask,5-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropylimidazolidine-2,4-dione(200 mg, 0.508 mmol, 1 eq.) was dissolved in acetonitrile (10 mL),methanol (10 mL), 1-bromopyrrolidine-2,5-dione (135 mg, 0.758 mmol, 1.5eq.), 2,2,2-trifluoroacetic acid (0.3 mL). The mixture was stirred for16 h at 60° C. The mixture was concentrated under vacuum. The residuewas applied onto a silica gel column with PE/EA (1/2) to yield5-(5-bromo-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropylimidazolidine-2,4-dioneas a yellow solid.

Mass spectrum (ESI, m/z): Calculated For C₂₂H₁₉BrFN₃O₃, 472.1 (M+H),found 472.1.

Step 2:5-(6-(8-fluoronaphthalen-2-yl)-2-methoxy-5-methylpyridin-3-yl)-5-isopropylimidazolidine-2,4-dione

Into 50 ml 3-rounds-bottom flask purged and maintained with an inertatmosphere of nitrogen,5-(5-bromo-6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropylimidazolidine-2,4-dione(200 mg, 0.423 mmol, 1 eq.) was dissolved in DMF (15 mL). Pd(OAc)₂ (9.5mg, 0.042 mmol, 0.1 eq.), (O-Tol)₃P (12.8 mg, 0.042 mmol, 0.1 eq.) andtetramethylstannane (113.7 mg, 0.636 mmol, 1.5 eq.) were then added. Themixture was stirred for 16 h at 100° C. The mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withPE/EA (1/3) to yield5-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropyl-1-methylimidazolidine-2,4-dioneas yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₂FN₃O₃, 408.2 (M+H), found408.2.

Step 3:(E)-6-(8-fluoronaphthalen-2-yl)-3-(4-isopropyl-2-(methoxyimino)imidazolidin-4-yl)-5-methylpyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 209 by reduction, sulfonation and displacement with methoxyamidefollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (300 MHz, CD₃OD) δ: 8.39 (s, 1H), 8.05 (d, J=8.7 Hz, 1H),7.81-7.84 (m, 1H),7.74 (d, J=8.1 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H),7.49-7.56 (m, 1H), 7.24-7.30 (m, 1H), 6.81 (d, J=7.5 Hz, 1H), 4.15 (d,J=11.4Hz, 1H), 3.97 (d, J=11.1Hz, 1H), 3.82 (s, 3H), 3.38 (s, 3H),2.69-2.86 (m, 1H), 1.04 (d, J=6.6 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H). ¹⁹FNMR (300 MHz, CD₃OD) δ: −77.03, −124.46. Mass spectrum (ESI, m/z):Calculated for C_(29.2)H_(28.1)F_(10.3)N₄O_(8.2), 409.2(M+H−3.10CF₃COOH), found 409.2.

Example 213 Compound #2946-(8-fluoronaphthalen-2-yl)-3-(4-isopropyl-5-oxo-2-thioxoimidazolidin-4-yl)pyridin-2(1H)-one

Step 1:5-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropyl-2-thioxoimidazolidin-4-one

Into 100 ml round-bottom flask,5-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropylimidazolidine-2,4-dione(500 mg, 1.271 mmol, 1.0 eq.) was dissolved in toluene (30 mL), andLawesson's Reagent (1.54 g, 3.807 mmol, 3.0 eq.) was added. The mixturewas stirred for 16 h at 100° C. The mixture was concentrated undervacuum. The residue was applied onto a silica gel column with PE/EA(3/1) to yield5-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-5-isopropyl-2-thioxoimidazolidin-4-oneas yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₀FN₃O₂S, 410.1 (M+H),found 410.1.

Step 2:6-(8-fluoronaphthalen-2-yl)-3-(4-isopropyl-5-oxo-2-thioxoimidazolidin-4-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product asa white solid.

¹H NMR (300 MHz, DMSO-d₆) δ: 9.81 (s, 1H), 8.46 (s, 1H), 8.12 (d, J=8.1Hz, 1H), 7.93-7.94 (m, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.56-7.71 (m, 2H),7.39-7.45 (m, 1H), 6.79 (brm, 1H), 2.71-2.85 (m, 1H), 0.92-0.97 (m, 6H).¹⁹F NMR (300 MHz, DMSO-d₆) δ: −72.61,−121.23. Mass spectrum (ESI, m/z):Calculated for C₂₁H₁₈FN₃O₂S, 396.1 (M−6.357CF3COOH+H), found 396.1.

Example 214 Compound #236 N-(4-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-isopropyl-5-oxo-4,5-dihydro-1H-imidazol-2-yl)cyanamide

The title compound was prepared according to the procedure described inExample 198 by displacement with cyanoamide followed by demethylationwith TMSCl/NaI to yield the product as a white solid.

¹H NMR (300 MHz, DMSO) δ: 12.36 (s, 1H), 11.84 (s, 1H), 9.50 (s, 1H),8.53 (s, 1H), 8.20 (d, J=10.8 Hz, 1H), 7.86-8.08 (m, 1H), 7.83 (d, J=8.1Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.56-7.63 (m, 1H), 7.39-7.45 (m, 1H),6.74-6.89 (m, 1H), 2.65-2.72 (m, 1H), 0.90-1.04 (t, J=8.1 Hz, 6H). ¹⁹FNMR (300 MHz, DMSO) δ: −73.88, −122.03. Mass spectrum (ESI, m/z):Calculated for C_(22.17)H_(18.085)F_(1.255)N₅O_(2.17), 404.1 (M−0.085CF₃COOH+H), found 404.0.

Example 215 Compound #237(Z)-6-(8-fluoronaphthalen-2-yl)-3-(4-isopropyl-2-(methoxyimino)-5-oxoimidazolidin-4-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 198 by displacement with methoxyamine followed by demethylationwith TMSCl/NaI to yield the product as a white solid.

¹H NMR (300 MHz, DMSO) δ: 12.40 (brs, 1H), 10.97 (brs, 1H), 8.44 (s,1H), 8.11-8.13 (m, 1H), 7.82-7.94 (m, 3H), 7.75 (brs, 1H), 7.55-7.61 (m,1H), 7.38-7.44 (m, 1H), 6.87 (brm, 1H), 3.62 (s, 3H), 2.27-2.50 (m, 1H),0.89-0.93 (m, 6H). ¹⁹F NMR (300 MHz, DMSO) δ: −73.97, −122.05. Massspectrum (ESI, m/z): Calculated forC_(22.838)H_(21.419)F_(2.257)N₄O_(3.838), 409.2 (M−0.419CF₃COOH+H),found 409.1.

Example 216 Compound #1553-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-isopropyl-1H-imidazo[1,2-a]imidazol-2(3H)-one

The title compound was prepared according to the procedure described inExample 208 to yield the product as an off-white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.45 (s, 1H), 8.09 (d, J=8.4 Hz, 1H),7.86-7.93 (m, 2H), 7.78 (d, J=8.0 Hz, 1H), 7.53-7.59 (m, 1H), 7.05-7.32(m, 2H), 6.77-6.84 (m, 2H), 3.32-3.33 (m, 1H), 0.70-1.03 (m, 6H). ¹⁹FNMR (400 MHz, CD₃OD) δ: −124.34. Mass spectrum (ESI, m/z): Calculatedfor C₂₃H₁₉FN₄O₃, 403.1 (M+H), found 403.1.

Example 217 Compound #2494-methyl-3-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)pentanamide

Step 1:3-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-4-methylpentanamide

Into a 50-mL round-bottom flask, were placed3-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-4-methylpentanoic acid (90mg, 0.258 mmol, 1.00 equiv.), DMF (3 mL), DCM (3 mL), ammonium chloride(68 mg, 1.271 mmol, 5 equiv.),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (490 mg, 1.289 mmol, 5 equiv.),N-ethyl-N-isopropylpropan-2-amine (166 mg, 1.284 mmol, 5 equiv.). Theresulting solution was stirred for 5 h at 25° C. The reaction progresswas monitored by LCMS. The reaction was then quenched by the addition ofwater (10 mL). The resulting solution was extracted with ethyl acetate(3×30 mL) and the organic layers combined. The resulting mixture waswashed with brine (1×30 mL). The mixture was dried over anhydrous sodiumsulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:2) to yield3-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-4-methylpentanamide as alight yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₄N₂O₂, 349.2 (M+H), found349.1.

Step 2:4-methyl-3-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)pentanamide

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product asa light yellow oil.

¹H NMR (300 MHz, CD₃OD) δ: 8.21 (s, 1H), 7.98-8.01 (m, 2H), 7.91-7.94(m, 1H), 7.74-7.78 (m, 1H), 7.56-7.60 (m, 2H), 7.50 (d, J=7.2 Hz, 1H),6.74 (d, J=7.2 Hz, 1H), 3.08-3.17 (m, 1H), 2.66-2.70 (m, 2H), 2.11-2.18(m, 1H), 1.01 (d, J=6.9 Hz, 3H), 0.91 (d, J=6.9 Hz, 3H). Mass spectrum(ESI, m/z): Calculated for C₂₁H₂₂N₂O₂, 335.2 (M+H), found 335.1.

Example 218 Compound #2504-methyl-N-(methylsulfonyl)-3-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)pentanamide

Step 1:3-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-4-methyl-N-(methylsulfonyl)pentanamide

Into a 50-mL round-bottom flask, were placed3-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-4-methylpentanoic acid (90mg, 0.258 mmol, 1.00 equiv.), DCM (5 mL), methanesulfonamide (49 mg,0.515 mmol, 2 equiv.), N,N-dimethylpyridin-4-amine (63 mg, 0.516 mmol, 2equiv.), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (99 mg, 0.516 mmol, 2 equiv.). The resulting solution wasstirred for 5 h at 25° C. The reaction progress was monitored by LCMS.The reaction was then quenched by the addition of water (10 mL). Theresulting solution was extracted with ethyl acetate (3×30 mL) and theorganic layers combined. The resulting mixture was washed with brine(1×20 mL). The mixture was dried over anhydrous sodium sulfate. Thesolids were filtered out. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:2) to yield3-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-4-methyl-N-(methylsulfonyl)pentanamideas a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₆N₂O₄S, 427.2 (M+H), found427.2.

Step 2:4-methyl-N-(methylsulfonyl)-3-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)pentanamide

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product asa light yellow oil.

¹H NMR (300 MHz, CD₃OD) δ: 8.21 (s, 1H), 7.97-8.01 (m, 2H), 7.91-7.94(m, 1H), 7.59-7.60 (m, 1H), 7.54-7.58 (m, 2H), 7.50 (d, J=7.2 Hz, 1H),6.75 (d, J=7.2 Hz, 1H), 3.11-3.20 (m, 1H), 3.08 (s, 3H), 2.78 (d, J=7.5Hz, 2H), 2.11-2.21 (m, 1H), 1.01 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz,3H).

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₄N₂O₄S, 413.1 (M+H), found413.2.

Example 219 Compound #2203-methyl-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanamide

Step 1: 2-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-3-methylbutanoicacid

The title compound was prepared by hydrolysis of ethyl2-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-3-methylbutanoate withNaOH to yield the product as a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₁NO₃, 336.2 (M+H), found336.4.

Step 2: 2-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)-3-methylbutanamide

The title compound was prepared by aminolysis with SOCl₂ and NH₃/MeOHsolution to yield the product as light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₂N₂O₂, 335.2 (M+H), found335.2.

Step 3:3-methyl-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanamide

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product asa light yellow solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.24 (s, 1H), 8.02 (d, J=8.0 Hz, 2H),7.93-7.95 (m, 1H), 7.78-7.84 (m, 2H), 7.58-7.60 (m, 2H), 6.83 (d, J=7.2Hz, 1H), 3.55 (d, J=10.4 Hz, 1H), 2.35-2.46 (m, 1H), 1.10 (d, J=6.4 Hz,3H), 0.88 (d, J=6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₀H₂₀N₂O₂, 321.2 (M+H), found 321.3.

Example 220 Compound #2213-methyl-N-(methylsulfonyl)-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanamide

The title compound was prepared according to the procedure described inExample 218 by coulping with methanesulfonamide followed bydemethylation with TMSCl/NaI to yield the product as a light yellow oil.

¹H NMR (400 MHz, CD₃OD) δ: 8.22 (s, 1H), 7.98-8.01 (m, 2H), 7.93-7.94(m, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.55-7.59 (m,2H), 6.82 (d, J=7.5 Hz, 1H), 3.62 (d, J=10.2 Hz, 1H), 3.10 (s, 3H),2.35-2.46 (m, 1H), 1.12 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.6 Hz, 3H). Massspectrum (ESI, m/z): Calculated for C₂₁H₂₂N₂O₄S, 399.1 (M+H), found399.2.

Example 221 Compound #2191-(6-(naphthalen-2-yl)-2-oxo-2,3-dihydropyridin-3-yl)cyclopentanecarboxamide

Step 1: Ethyl1-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)cyclopentanecarboxylate

Into a 8-mL vial purged and maintained with nitrogen, were placed ethyl2-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)acetate (100 mg, 0.3 mmol,1 equiv.), DMF (4 mL), t-BuOK (1 mL, 1 mmol, 3 equiv.),1,4-dibromobutane (215 mg, 1 mmol, 3 equiv.). The resulting solution wasstirred for 3 h at 25° C. The resulting solution was diluted with H₂O.The resulting solution was extracted with EtOAc and the organic layerscombined and concentrated under vacuum. The residue was purified by TLCwith PE:EA=12/1 to yield ethyl1-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)cyclopentanecarboxylate asyellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₅NO₃, 376.2 (M+H), found376.2.

Step 2:1-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)cyclopentanecarboxylic acid

Into a 100-mL round bottle were placed ethyl1-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)cyclopentanecarboxylate(150 mg, 0.4 mmol, 1 equiv.), KOH (500 mg, 8.9 mmol, 20 equiv.), THF (5mL), H₂O (5 mL), EtOH (5 mL). The resulting solution was stirred for 2 dat 100° C. The pH value of the solution was adjust to 6 with HCl (con.).The resulting solution was extracted with EtOAc and the organic layerscombined and concentrated under vacuum to yield1-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)cyclopentanecarboxylic acidas yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₁NO₃, 348.2 [M+H]⁺, found348.1.

Step 3: Ethyl1-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)cyclopentanecarboxylate

Into a 100-mL round bottle were placed1-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)cyclopentanecarboxylic acid(190 mg, 0.54 mmol, 1 equiv.), NH₄Cl (60 mg, 1.1 mmol, 2 equiv.), HATU(420 mg, 1.1 mmol, 2 equiv.), DIEA (150 mg, 1.1 mmol, 2 equiv.), DMF (5mL), DCM (5 mL). The resulting solution was diluted with H₂O. Theresulting solution was extracted with DCM and the organic layerscombined and concentrated under vacuum. The residue was purified by TLCwith PE:EA=1/1 to yield ethyl1-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)cyclopentanecarboxylate asyellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₂N₂O₂, 347.2 [M+H]⁺, found347.1.

Step 4:1-(6-(naphthalen-2-yl)-2-oxo-2,3-dihydropyridin-3-yl)cyclopentanecarboxamide

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product asa yellow solid.

¹H NMR (300 MHz, DMSO-d₆, ppm) δ: 8.37 (s, 1H), 7.96-8.02 (m, 3H),7.84-7.86 (m, 1H), 7.58-7.60 (m, 2H), 7.46-7.48 (m, 1H), 6.89-6.96 (m,1H), 6.63-6.71 (m, 2H) 2.33-2.35 (m, 2H), 1.85-1.88 (m, 2H), 1.57-1.65(m, 4H).

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₀N₂O₂, 355.2 [M+Na]⁺,found 355.1.

Example 222 Compound #2322,3-dimethyl-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanamide

Step 1: Ethyl1-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)cyclopentanecarboxylate

Into a 100-mL round bottle purged and maintained with nitrogen, wereplaced ethyl 2-(2-methoxy-6-(naphthalen-2-yl)pyridin-3-yl)acetate (300mg, 0.825 mmol, 1 equiv.), DMF (5 mL), t-BuOK (1.6 mL, 1.6 mmol, 2equiv.), iodomethane (340 mg, 2.4 mmol, 3 equiv.). The resultingsolution was stirred for 16 h at 25° C. The resulting solution wasdiluted with H₂O. The resulting solution was extracted with EtOAc andthe organic layers combined and concentrated under vacuum. The residuewas purified by silica gel column with PE:EA=90/10 to yield ethyl1-(2-methoxy-6-(naphthalen-2-yl) pyridin-3-yl)cyclopentanecarboxylate asyellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₇NO₃, 378.2 (M+H), found378.2.

Step 2:2,3-dimethyl-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanamide

The title compound was prepared according to the procedure described inExample 221 by hydrolysis, aminolysis followed by demethylation withTMSCl/NaI to yield the product as a white solid.

¹H NMR (300 MHz, Methanol-d₄, ppm) δ: 8.31 (s, 1 H), 7.91-8.02 (m, 3H),7.78 (d, J=7.5 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.55-7.59 (m, 2H), 6.79(d, J=7.5 Hz, 1H), 3.08-3.17 (m, 1H), 1.59 (s, 3H), 1.06 (d, J=6.6 Hz,3H), 0.86 (d, J=6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₁H₂₂N₂O₂, 357.2 [M+Na]⁺, found 357.1.

Example 223 Compound #175N-(4,5-dichlorothiophen-2-ylsulfonyl)-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide

Step 1:2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanoicacid

Into a 50-mL round-bottom flask, were placed ethyl2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanoate(40 mg, 0.105 mmol, 1.0 equiv.), KOH (73 mg, 1.304 mmol, 10 equiv.), THF(1 mL), EtOH (1 mL), H₂O (1 mL). The resulting solution was stirred for1 h at 100° C. in an oil bath. The reaction progress was monitored byLCMS. The resulting mixture was concentrated under vacuum. The reactionwas dilute by the addition of water. The resulting solution wasextracted with diethyl ether (3×20 mL) and the water layers combined andadjust pH=3 by HCl (2N). Then the resulting solution was extracted withethyl acetate (3×20 mL) and the organic layers combined. The mixture wasdried over anhydrous sodium sulfate. The solids were filtered out. Theresulting mixture was concentrated under vacuum to yield2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanoicacid as a yellow oil.

Mass spectrum (ESI, m/z): Calculated For C₂₁H₂₀FNO₃, 354.1 (M+H), found354.2.

Step 2:N-(4,5-dichlorothiophen-2-ylsulfonyl)-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 218 by coulping with m 4,5-dichlorothiophene-2-sulfonamidefollowed by demethylation with TMSCl/NaI to yield the product asoff-white solid.

¹H NMR (300 MHz, DMSO-d₆) δ: 8.38-8.49 (m, 1H), 8.10-8.17 (m, 1H),7.81-7.98 (m, 1H), 7.70-7.85 (m, 2H), 7.50-7.65 (m, 2H), 7.32-7.49 (m,1H), 7.79-7.95 (m, 1H), 3.61-3.75 (m, 1H), 2.15-2.30 (m, 1H), 0.63-0.94(m, 6H). ¹⁹F NMR (300 MHz, DMSO-d₆) δ: −122.19. Mass spectrum (ESI,m/z): Calculated For C₂₄H₁₉C₁₂FN₂O₄S₂, 553.0 (M+H), found 553.0.

Example 224 Compound #2392-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-N-isopropyl-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with i-Pr—NH₂ followed by demethylation withTMSCl/NaI to yield the product as a yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ: 8.48 (s, 1H), 8.10 (d, J=8.1 Hz, 1H),7.97-7.99 (m, 2H), 7.83 (d, J=8.4 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H),7.53-7.60 (m, 1H), 7.37-7.43 (m, 1H), 6.86-6.91 (m, 1H), 3.76-3.88 (m,1H), 3.51 (d, J=10.2 Hz, 1H), 2.08-2.19 (m, 1H), 1.02-1.28 (m, 9H), 0.99(d, J=5.4 Hz, 3H). ¹⁹F NMR (300 MHz, DMSO-d₆) δ: −74.54, −122.27. Massspectrum (ESI, m/z): Calculated ForC_(23.216)H_(25.108)F_(1.324)N₂O_(2.216), 381.2 (M−0.108CF₃COOH+H),found 381.1.

Example 225 Compound #1762-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methyl-N-(thiazol-2-yl)butanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-aminothiazole followed by demethylationwith TMSCl/NaI to yield the product as a yellow solid.

¹H NMR (300 MHz,DMSO-d₆) δ: 12.35 (s, 1H), 8.48 (s, 1H), 8.11 (d,J=7.8Hz, 1H), 7.95-7.98 (m, 1H), 7.75-7.84 (m, 2H), 7.52-7.61 (m, 1H),7.41-7.47 (m, 2H), 7.21-7.27 (m, 1H), 6.84-6.93 (m, 1H), 3.97 (d,J=9.9Hz, 1H), 2.33-2.43 (m, 1H), 0.90-1.03 (m, 3H), 0.79-0.88 (m, 3H).¹⁹F NMR (300 MHz, DMSO-d₆) δ: −122.21, −74.36. Mass spectrum (ESI, m/z):Calculated For C_(24.17)H_(20.585)F_(2.755)N₃O_(3.17)S, 422.1(M−0.585CF₃COOH+H), found 422.1.

Example 226 Compound #256N-(4,5-dichlorothiophen-2-ylsulfonyl)-3-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-methylpentanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 4,5-dichlorothiophene-2-sulfonamidefollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (400 MHz,CD₃OD) δ: 8.39 (s, 1H), 8.06 (d, J=8.0 Hz, 1H),7.81-7.86 (m, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.52-7.58 (m, 1H), 7.42-7.44(m, 1H), 7.27-7.32 (m, 2H), 6.62-6.64 (m, 1H), 3.24-3.32 (m, 1H),2.59-2.65 (m, 2H), 2.06-2.11 (m, 1H), 0.90-0.95 (m, 6H). ¹⁹F NMR (400MHz, CD₃OD) δ: −76.99, −124.37. Mass spectrum (ESI, m/z): Calculated ForC_(26.68)H_(21.84)C₁₂F_(3.52)N₂O_(5.68)S₂, 567.0 (M−0.84CF₃COOH+H),found 567.0.

Example 227 Compound #2513-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-methylpentanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with ammonia followed by demethylation withTMSCl/NaI to yield the product as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.42 (s, 1H), 8.08 (d, J=8.4 Hz, 1H),7.85-7.88 (m, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.52-7.60 (m, 2H), 7.28-7.34(m, 1H), 6.78 (d, J=7.2 Hz, 1H), 3.11-3.21 (m, 1H), 2.66-2.76 (m, 2H),2.13-2.20 (m, 1H), 1.03 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H). ¹⁹FNMR (300 MHz, CD₃OD) δ: −77.49, −124.57. Mass spectrum (ESI, m/z):Calculated for C_(23.66)H_(22.33)F_(4.99)N₂O_(4.66), 353.2(M−1.33CF₃COOH+H), found 353.2.

Example 228 Compound #2282-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-N-methoxy-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with hydroxylamine HCl followed by demethylationwith TMSCl/NaI to yield the product as a white solid.

¹H NMR (400 Hz, CD₃OD) δ: 8.43 (s, 1H), 8.08 (d, J=8.8 Hz,1H), 7.88-7.93(m, 2H), 7.78 (d, J=8.4 Hz,1H), 7.53-7.58 (m, 1H), 7.28-7.33 (m, 1H),6.84 (d, J=7.2 Hz,1H), 3.69 (s, 3H), 3.43-3.69 (m, 1H), 2.31-2.39 (m,1H), 1.10 (d, J=6.8 Hz,3H), 0.89 (d, J=6.8 Hz,3H). ¹⁹F NMR (400 Hz,CD₃OD) δ: −124.41.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₁FN₂O₃, 369.2 (M+H), found369.1.

Example 229 Compound #2573-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-N-methoxy-4-methylpentanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with hydroxylamine HCl followed by demethylationwith TMSCl/NaI to yield the product as a yellow semi solid.

¹H NMR (400 MHz,CD₃OD) δ: 8.40 (s, 1H), 8.07 (d, J=8.4 Hz, 1H),7.84-7.87 (m, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.53-7.58 (m, 1H), 7.31-7.33(m, 1H), 7.28-7.30 (m, 1H), 6.76 (d, J=7.2 Hz, 1H), 3.53 (s, 3H),3.06-3.10 (m, 1H), 2.56 (d, J=7.6 Hz, 2H), 2.17-2.25 (m, 1H), 1.03 (d,J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD) δ:−77.47, −124.56. Mass spectrum (ESI, m/z): Calculated ForC_(23.58)H_(23.79)F_(3.37)N₂O_(4.58), 383.2 (M−0.79CF₃COOH+H), found383.1.

Example 230 Compound #2342-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-N-(2-hydroxyethyl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-hydroxy-ethylamine followed bydemethylation with TMSCl/NaI to yield the product as an off white solid.

Mass spectrum (ESI, m/z): Calculated For C₂₄H₂₄F₄N₂O₅, 383.2(M−0.41CF₃COOH+H), found 383.1.

Example 231 Compound #2583-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-N-(2-hydroxyethyl)-4-methylpentanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-hydroxy-ethylamine followed bydemethylation with TMSCl/NaI to yield the product as an off white solid.

¹H NMR (400 MHz,CD₃OD) δ: 8.41 (s, 1H), 8.06-8.08 (m, 1H), 7.85-7.87 (m,1H), 7.77 (d, J=8.0 Hz, 1H), 7.51-7.58 (m, 2H), 7.28-7.32 (m, 1H), 6.77(d, J=7.2 Hz, 1H), 3.44-3.49 (m, 2H), 3.12-3.22 (m, 3H), 2.67-2.69 (m,2H), 2.13-2.19 (m, 1H), 1.03 (d, J=6.8 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H).¹⁹F NMR (400 MHz, CD₃OD) δ: −77.61, −124.53. Mass spectrum (ESI, m/z):Calculated For C_(24.96)H_(25.98)F_(3.94)N₂O_(4.96), 397.2(M−0.98CF₃COOH+H), found 397.1.

Example 232 Compound #2671-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)urea

Step 1:2-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)isoindoline-1,3-dione

Into a 50-mL round-bottom flask, were placed1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-ol(325 mg, 0.999 mmol, 1.0 equiv.), isoindoline-1,3-dione (441 mg, 2.997mmol, 3.0 equiv.), DIAD (606 mg, 3 mmol, 3.0 equiv.), PPh₃ (786 mg, 3mmol, 3.0 equiv.), THF (20 mL). The resulting solution was stirred 1.0 hat room temperature. The reaction progress was monitored by LCMS. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (40/60) toyield2-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)isoindoline-1,3-dioneas a white solid.

Mass spectrum (ESI, m/z): Calculated For C₂₈H₂₃FN₂O₃, 455.2 (M+H), found455.2.

Step 2:1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-amine

Into a 50-mL round-bottom flask, were placed2-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)isoindoline-1,3-dione(190 mg, 0.418 mmol, 1.0 equiv.), MeOH (20 mL), NH₂NH₂ (0.5 mL). Theresulting solution was stirred 3.0 h at room temperature. The reactionprogress was monitored by LCMS. The resulting solution was concentratedunder vacuum. The residue was applied TLC with DCM:MeOH=20:1 to yield1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-amineas a brown oil.

Mass spectrum (ESI, m/z): Calculated For C₂₀H₂₁FN₂O, 325.2 (M+H), found325.0.

Step 3:1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)urea

Into a 50-mL round-bottom flask, were placed1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-amine(20 mg, 0.062 mmol, 1.0 equiv.), THF (3 mL), AcOH (0.1 mL), KCNO (10 mg,0.123 mmol, 2.0 equiv.), H₂O (1 mL). The resulting solution was stirredovernight at room temperature. The reaction progress was monitored byLCMS. The resulting solution was concentrated under vacuum. The residuewas applied TLC with PE:EA=3:1 to yield1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)ureaas a brown oil.

Mass spectrum (ESI, m/z): Calculated For C₂₁H₂₂FN₃O₂, 368.2 (M+H), found368.1.

Step 4: 1-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methyl propyl)urea

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product asa white solid.

¹H NMR (400 MHz,CD₃OD) δ: 8.41 (s, 1H), 8.07 (d, J=8.0 Hz, 1H),7.85-7.87 (m, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.52-7.58 (m, 2H), 7.28-7.30(m, 1H), 6.77 (d, J=7.2 Hz, 1H), 4.54-4.55 (m, 1H), 2.29-2.37 (m, 1H),1.00 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD)δ: −124.49.

Mass spectrum (ESI, m/z): Calculated For C₂₀H₂₀FN₃O₂, 354.2 (M+H), found354.0.

Example 233 Compound #2532-((6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methylbutanamide

Step 1: ethyl2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutanoate

Into a 25-ml round-bottom flask purged and maintained with an inertatmosphere of nitrogen were added ethyl2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutanoate(100 mg, 0.283 mmol, 1.00 equiv.) in dry THF (8 mL), then LDA (0.3 ml,0.6 mmol, 2.0 equiv.) via syringe at −78° C. The resulting solution wasstirred at −78° C. for 1.5 hour, and then Isopropyl iodide (0.06 ml,0.596 mmol, 2.0 equiv.) was added at −78° C. and the mixture was stirredat this temperature for 1.5 h. The reaction mixture was stirredovernight allowing to warm to room temperature. The reaction wasmonitored by LCMS. The resulting solution was extracted with ethylacetate. The organic layers were combined and concentrated under vacuum.The residue was applied on a silica gel column and eluted with EA/PE(1:10) to yield ethyl2-((6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)methyl)-3-methylbutanoateas a yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₆FNO₃, 396.2 (M+H), found396.1.

Step 2:2-((6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 219 by hydrolysis, aminolysis followed by demethylation withTMSCl/NaI to yield the product as a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.38 (s, 1H), 8.06 (d, J=8.4 Hz,1H), 7.84 (d,J=10.0 Hz,1H), 7.77 (d, J=8.0 Hz,1H), 7.52-7.59 (m, 2H), 7.28-7.32 (m,1H), 6.73 (d, J=7.2 Hz,1H), 2.95-3.03 (m, 1H), 2.48-2.63 (m, 2H),1.90-1.94 (m, 1H), 1.13 (d, J=6.8 Hz, 3H), 1.07 (d, J=6.8 Hz, 3H). ¹⁹FNMR (400 MHz, CD₃OD) δ: −124.62. Mass spectrum (ESI, m/z): Calculatedfor C₂₁H₂₁FN₂O₂, 353.2 (M+H), found 353.0.

Example 234 Compound #227N-(2-(dimethylamino)ethyl)-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-dimethylamino-ethylamine followed bydemethylation with TMSCl/NaI to yield the product as a yellow solid.

¹H NMR (300 MHz,CD₃OD) δ: 8.07 (s, 1H), 8.04 (d, J=7.2 Hz, 1H),7.74-7.84 (m, 3H), 7.51-7.57 (m, 1H), 7.24-7.28 (m, 1H), 6.86 (d, J=7.5Hz, 1H), 3.71-3.80 (m, 1H), 3.33-3.45 (m, 2H), 3.19-3.29 (m, 2H), 3.10(d, J=8.4 Hz, 6H), 2.36-2.44 (m, 1H), 1.06 (d, J=6.6 Hz, 3H), 0.93 (d,J=6.6 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −77.25, −124.53. Massspectrum (ESI, m/z): Calculated for C_(28.68)H_(37.36)FN₃O_(6.68), 410.2[M−2.43CF₃COOH+H], found 410.3.

Example 235 Compound #2382-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-(2-(2-methoxyethoxy)ethoxy)ethan-1-aminefollowed by demethylation with TMSCl/NaI to yield the product as a lightyellow oil.

¹H NMR (300 MHz, CD₃OD) δ: 8.38 (s, 1H), 8.02 (d, J=7.8 Hz, 1H),7.71-7.83 (m, 3H), 7.47-7.55 (m, 1H), 7.23-7.29 (m, 1H), 6.78 (d, J=7.2Hz, 1H), 3.45-3.57 (m, 11H), 3.31-3.34 (m, 1H), 3.27-3.28 (m, 4H),2.33-2.37 (m, 1H), 1.04 (d, J=6.6 Hz, 3H), 0.83 (d, J=6.6 Hz, 3H). ¹⁹FNMR (300 MHz, CD₃OD) δ: −124.43. Mass spectrum (ESI, m/z): Calculatedfor C₂₇H₃₃FN₂O₅, 485.2 [M+H]⁺, found 485.4.

Example 236 Compound #1742-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methyl-N-(tetrahydro-2H-pyran-4-yl)butanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with tetrahydro-2H-pyran-4-amine followed bydemethylation with TMSCl/NaI to yield the product as a yellow solid.

¹H NMR (300 MHz,CD₃OD) δ: 8.38 (s, 1H), 8.03 (d, J=7.2 Hz, 1H),7.79-7.83 (m, 2H), 7.73 (d, J=8.1 Hz, 1H), 7.47-7.52 (m, 1H), 7.23-7.28(m, 1H), 6.79 (d, J=7.5 Hz, 1H), 3.83-3.91 (m, 3H), 3.38-3.49 (m, 3H),2.22-2.31 (m, 1H), 1.81-1.82 (m, 1H), 1.68-1.70 (m, 1H), 1.44-1.52 (m,2H), 1.04 (d, J=6.6 Hz, 3H), 0.81 (d, J=6.6 Hz, 3H). ¹⁹F NMR (300 MHz,CD₃OD) δ: −77.41, −124.43. Mass spectrum (ESI, m/z): Calculated forC_(25.2)H_(27.4)FN₂O_(3.2), 423.2[M−0.1CF3COOH+H], found 423.2.

Example 237 Compound #177N-(azetidin-3-yl)-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide

Step 1:N-(azetidin-3-yl)-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanamide

Into a 50-mL round-bottom flask, were placed tert-butyl3-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanamido)azetidine-1-carboxylate(100 mg, 0.197 mmol, 1.0 equiv.), TFA (1 mL), DCM (4 mL). The resultingsolution was stirred overnight at room temperature. The reactionprogress was monitored by LCMS. The resulting mixture was concentratedunder vacuum. The residue was applied TLC with MeOH:DCM=1:10 to yieldN-(azetidin-3-yl)-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanamideas a brown oil.

Mass spectrum (ESI, m/z): Calculated For C₂₄H₂₆FN₃O₂, 408.2 (M+H), found408.1.

Step 2:N-(azetidin-3-yl)-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product asan orange solid.

¹H NMR (300 MHz,CD₃OD) δ: 8.36 (s, 1H), 8.02-8.06 (m, 1H), 7.72-7.83 (m,3H), 7.49-7.56 (m, 1H), 7.23-7.30 (m, 1H), 6.80 (d, J=7.5 Hz, 1H),4.55-4.63 (m, 1H), 4.23-4.29 (m, 2H), 4.06-4.20 (m, 2H), 3.53 (d, J=10.8Hz, 1H), 2.33-2.41 (m, 1H), 1.05 (d, J=6.3 Hz, 3H), 0.85 (d, J=6.9 Hz,3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −77.22, −124.52. Mass spectrum (ESI,m/z): Calculated For C_(28.3)H_(26.65)F_(8.95)N₃O_(7.3), 394.2(M−2.65CF₃COOH+H), found 394.2.

Example 238 Compound #2603-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-N-isopropyl-4-methylpentanamid

The title compound was prepared according to the procedure described inExample 221 by coulping with i-Pr—NH₂ followed by demethylation withTMSCl/NaI to yield the product as white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.38 (s, 1H), 8.04-8.07 (m, 1H), 7.75-7.85(m, 2H), 7.45-7.58 (m, 2H), 7.26-7.32 (m, 1H), 6.73 (d, J=7.2 Hz, 1H),3.79-3.90 (m, 1H), 3.02-3.10 (m, 1H), 2.57-2.63 (m, 2H), 2.11-2.23 (m,1H), 1.00-1.06 (m, 6H), 0.88-0.94 (m, 6H). ¹⁹F NMR (400 MHz, CD₃OD) δ:−125.00. Mass spectrum (EI, m/z): Calculated for C₂₃H₂₅NO₄, 395.2 (M+H),found 395.2.

Example 239 Compound #259N-(2-(dimethylamino)ethyl)-3-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-methylpentanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-dimethylamino-ethylamine followed bydemethylation with TMSCl/NaI to yield the product as light yellow solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.41 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.86(d, J=8.8 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.53-7.59 (m, 1H), 7.49 (d,J=7.2 Hz, 1H), 7.28-7.33 (m, 1H), 6.77 (d, J=7.2 Hz, 1H), 3.15-3.34 (m,2H), 3.07-3.13 (m, 1H), 2.66-2.68 (m, 2H), 2.34-2.36 (m, 2H), 2.23 (s,6H), 2.15-2.23 (m, 1H), 1.04 (d, J=6.8 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H).¹⁹F NMR (400 MHz, CD₃OD) δ: −124.64. Mass spectrum (EI, m/z): Calculatedfor C₂₅H₃₀FN₃O₂, 424.2 (M+H), found 424.3.

Example 240 Compound #2543-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-N-(thiazol-2-yl)pentanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-aminothiazole followed by demethylationwith TMSCl/NaI to yield the product as light yellow solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.37 (s, 1H), 7.99-8.01 (m, 1H), 7.77-7.78(m, 1H), 7.68-7.74 (m, 2H), 7.51-7.55 (m, 1H), 7.33 (d, J=4.4 Hz, 1H),6.99 (d, J=3.6 Hz, 1H), 6.80 (d, J=6.4 Hz, 1H), 6.57 (d, J=9.2 Hz, 1H),3.60-3.65 (m, 1H), 3.10-3.15 (m, 1H), 2.95-3.02 (m, 1H), 2.11-2.12 (m,1H), 1.13 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H)¹⁹F NMR (400 MHz,CD₃OD) δ: −127.95. Mass spectrum (EI, m/z): Calculated for C₂₄H₂₂FN₃O₂S,436.1 (M+H), found 436.2.

Example 241 Compound #2613-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-N-(1H-imidazol-2-yl)-4-methylpentanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-aminoimidazole followed by demethylationwith TMSCl/NaI to yield the product as light yellow solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.38 (s, 1H), 8.04 (d, J=8.4 Hz, 1H),7.75-7.84 (m, 2H), 7.55-7.58 (m, 2H), 7.26-7.32 (m, 1H), 7.10 (s, 2H),6.76 (d, J=7.5 Hz, 1H), 3.01-3.33 (m, 1H), 2.99-3.01 (m, 2H), 2.13-2.22(m, 1H), 1.06 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.9 Hz, 3H). ¹⁹F NMR (300MHz, CD₃OD) δ: −76.92, −124.58. Mass spectrum (EI, m/z): Calculated forC_(28.62)H_(25.31)F_(7.93)N₄O_(6.62), 419.2 (M−2.31CF₃COOH+H), found419.1.

Example 242 Compound #1822-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methyl-N-(1-methylazetidin-3-yl)butanamide

Step 1:2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methyl-N-(1-methylazetidin-3-yl)butanamide

Into a 50-mL round-bottom flask, were placedN-(azetidin-3-yl)-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanamide(70 mg, 0.172 mmol, 1.0 equiv.), formaldehyde (6 mg, 0.200 mmol, 1.1equiv.), MeOH (10 mL), AcOH (0.2 mL). The resulting solution was stirred2.0 h at 80° C. Then placed NaBH(OAc)₃ (72 mg, 0.340 mmol, 2.0 equiv.).The resulting solution was stirred 3.0 h at 50° C. The reaction progresswas monitored by LCMS. The resulting mixture was concentrated undervacuum. The residue was applied TLC with PE:EA=1:1 to yield2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methyl-N-(1-methylazetidin-3-yl)butanamideas a brown oil.

Mass spectrum (ESI, m/z): Calculated For C₂₅H₂₈FN₃O₂, 422.2 (M+H), found422.3.

Step 2:2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methyl-N-(1-methylazetidin-3-yl)butanamide

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product aswhite solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.39 (s, 1H), 8.03 (d, J=8.7 Hz, 1H),7.72-7.84 (m, 3H), 7.50-7.55 (m, 1H), 7.23-7.29 (m, 1H), 6.79 (d, J=7.5Hz, 1H), 4.32-4.82 (m, 1H), 3.62-3.70 (m, 2H), 3.47-3.59 (m, 1H),2.93-3.04 (m, 2H), 2.28-2.35 (m, 4H), 1.02 (d, J=6.3 Hz, 3H), 0.83 (d,J=6.6 Hz, 3H). 19F NMR (300 MHz, CD₃OD) δ: −124.46. Mass spectrum (ESI,m/z): Calculated For C₂₄H₂₆FN₃O₂, 406.1 (M−H), found 406.1.

Example 243 Compound #229N-(2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethyl)-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide

Step 1:N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanamide

Into a 50-mL round-bottom flask, were placed tert-butyl2-(2-(2-(2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanamido)ethoxy)ethoxy)ethylcarbamate(80 mg, 0.137 mmol, 1.0 equiv.), DCM (12 mL), TFA (3 mL). The resultingsolution was stirred overnight at room temperature. The reactionprogress was monitored by LCMS. The resulting mixture was concentratedunder vacuum. The residue was applied TLC with MeOH:DCM=1:10 to yieldN-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanamideas a brown oil.

Mass spectrum (ESI, m/z): Calculated For C₂₇H₃₄FN₃O₄, 484.3 (M+H), found484.2.

Step 2:N-(2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethyl)-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanamide

Into a 8-mL closed tube, were placedN-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanamide(80 mg, 0.165 mmol, 1.0 equiv.), MeOH (10 mL), formaldehyde (37%) (1mL), AcOH (0.5 mL), NaBH(OAc)₃ (70 mg, 0.330 mmol, 2.0 equiv.). Theresulting solution was stirred overnight at 70° C. The reaction progresswas monitored by LCMS. The resulting mixture was concentrated undervacuum. The residue was applied TLC with PE:EA=1:1 to yieldN-(2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethyl)-2-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-methylbutanamideas a brown oil.

Mass spectrum (ESI, m/z): Calculated For C₂₉H₃₈FN₃O₄, 512.3 (M+H), found512.3.

Step 3:N-(2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethyl)-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product asa white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.38 (s, 1H), 8.03 (d, J=9.9 Hz, 1H),7.72-7.84 (m, 3H), 7.48-7.55 (m, 1H), 7.23-7.29 (m, 1H), 6.79 (d, J=7.5Hz, 1H), 3.47-3.55 (m, 9H), 3.27-3.34 (m, 2H), 2.47-2.51 (m, 2H),2.32-2.43 (m, 1H), 2.21 (s, 6H), 1.04 (d, J=6.6 Hz, 3H), 0.81 (d, J=6.9Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −124.45. Mass spectrum (ESI, m/z):Calculated For C₂₈H₃₆FN₃O₄, 496.3 (M−H), found 496.2.

Example 244 Compound #233N-(2-(2-(dimethylamino)ethoxy)ethyl)-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-(2-aminoethoxy)-N,N-dimethylethan-1-aminefollowed by demethylation with TMSCl/NaI to yield the product as brownoil.

¹H NMR (300 MHz, CD₃OD) δ: 8.37 (s, 1H), 8.02-8.06 (m, 1H), 7.72-7.83(m, 3H), 7.48-7.55 (m, 1H), 7.23-7.29 (m, 1H), 6.81 (d, J=7.2 Hz, 1H),3.71-3.74 (m, 2H), 3.41-3.57 (m, 5H), 3.27-3.40 (m, 2H), 2.88 (s, 6H),2.34-2.42 (m, 1H), 1.05 (d, J=6.6 Hz, 3H), 0.85 (d, J=6.4 Hz, 3H). ¹⁹FNMR (300 MHz, CD₃OD) δ: −76.88, −124.49. Mass spectrum (ESI, m/z):Calculated For C_(32.04)H_(35.02)F_(10.06)N₃O_(9.04), 454.2(M−3.02CF₃COOH+H), found 454.2.

Example 245 Compound #2416-(8-fluoronaphthalen-2-yl)-3-(2-methyl-1-(5-methyl-1H-imidazol-2-yl)propyl)pyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-dimethylamino-ethylamine followed bydemethylation with TMSCl/NaI to yield the product as a yellow solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.13 (s, 1H), 7.85-7.91 (m, 2H), 7.68-7.72(m, 2H), 7.30 (s, 1H), 7.18-7.22 (m, 1H), 6.82 (d, J=7.2 Hz, 1H), 3.93(s, 3H), 3.71-3.80 (m, 1H), 3.18-3.46 (m, 4H), 2.92 (s, 6H), 2.37-2.45(m, 1H), 1.07 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H). Mass spectrum(ESI, m/z): Calculated for C₂₅H₃₁N₃O₃, 422.2 (M+H), found 422.2.

Example 246 Compound #242N-(2-(dimethylamino)ethyl)-2-(6-(6-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-dimethylamino-ethylamine followed bydemethylation with TMSCl/NaI to yield the product as a light yellowsolid.

¹H NMR (300 MHz, CD₃OD) δ: 8.24 (s, 1H), 7.94-8.05 (m, 2H), 7.76-7.82(m, 2H), 7.55-7.59 (m, 1H), 7.33-7.40 (m, 1H), 6.88 (d, J=7.2 Hz, 1H),3.70-3.79 (m, 1H), 3.39-3.48 (m, 2H), 3.19-3.34 (m, 2H), 2.91 (d, J=7.2Hz, 6H), 2.39-2.43 (m, 1H), 1.05 (d, J=6.3 Hz, 3H), 0.89 (d, J=6.6 Hz,3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −75.52, −114.05. Mass spectrum (ESI,m/z): Calculated for C_(24.84)H_(28.42)F_(2.26)N₃O_(2.84), 410.2(M+H−0.42CF₃COOH), found 410.0.

Example 247 Compound #244N-(2-(dimethylamino)ethyl)-3-methyl-2-(6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-dimethylamino-ethylamine followed bydemethylation with TMSCl/NaI to yield the product as white solid.

¹H NMR (300 MHz, CD₃OD) δ: 7.68 (s, 1H), 7.18-7.22 (m, 1H), 7.08 (s,1H), 6.79 (d, J=8.4 Hz, 1H), 6.64 (d, J=7.5 Hz, 1H) 4.28-4.31 (m, 2H),3.72-3.79 (m, 1H), 3.20-3.46 (m, 6H), 2.90-2.97 (m, 9H), 2.39-2.42 (m,1H), 1.06 (d, J=6.0 Hz, 3H), 0.92 (d, J=6.9 Hz, 3H). Mass spectrum (ESI,m/z): Calculated for C₂₃H₃₂N₄O₃, 413.2 (M+H), found 413.2.

Example 248 Compound #302N-(2-(dimethylamino)ethyl)-3-methyl-2-(6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-dimethylamino-ethylamine followed bydemethylation with TMSCl/NaI to yield the product as a yellow solid.

¹H NMR (400 MHz, CD₃OD) δ: 7.72 (d, J=7.6 Hz, 1H), 6.92-6.98 (m, 2H),6.80 (d, J=8.0 Hz, 1H), 6.68 (d, J=7.2 Hz, 1H), 4.30-4.33 (m, 2H),3.72-3.78 (m, 1H), 3.40-3.47 (m, 2H), 3.20-3.33 (m, 5H), 2.89-2.96 (m,9H), 2.37-2.44 (m, 1H), 0.82 (d, J=8 Hz, 3H), 0.67 (d, J=8 Hz, 3H). Massspectrum (ESI, m/z): Calculated for C₂₃H₃₂N₄O₃, 413.2 (M+H), found413.2.

Example 249 Compound #2462-(6-(benzo[d]thiazol-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)-N-(2-(dimethylamino)ethyl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-dimethylamino-ethylamine followed bydemethylation with TMSCl/NaI to yield the product as white solid.

¹H NMR (300 MHz, CD₃OD) δ: 9.38 (s, 1H), 8.46 (s, 1H), 8.21 (d, J=8.7Hz, 1H), 7.87-7.90 (m, 1H), 7.82 (d, J=7.5 Hz, 1H), 6.79 (d, J=7.2 Hz,1H), 3.53 (d, J=10.8 Hz, 1H), 3.27-3.39 (m, 2H), 2.44-2.49 (t, J=6.9 Hz,2H), 2.35-2.43 (m, 1H), 2.28 (s, 6H), 1.08 (d, J=6.6 Hz, 3H), 0.94 (d,J=6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₆N₄O₂S,399.2 (M+H), found 399.1.

Example 250 Compound #2432-(6-(benzo[d]thiazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)-N-(2-(dimethylamino)ethyl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-dimethylamino-ethylamine followed bydemethylation with TMSCl/NaI to yield the product as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 9.33 (s, 1H), 8.36 (s, 1H), 8.20 (d, J=8.4Hz, 1H), 7.74-7.79 (m, 2H), 6.81 (d, J=7.2 Hz, 1H), 3.69-3.78 (m, 1H),3.32-3.45 (m, 2H), 3.20-3.28 (m, 2H), 2.91 (s, 6H), 2.36-2.45 (m, 1H),1.06 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H). Mass spectrum (ESI,m/z): Calculated for C₂₁H₂₆N₄O₂S, 399.2 (M+H), found 399.0.

Example 251 Compound #2651-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)-1-methylurea

Step 1:1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-N,2-dimethylpropan-1-amine

Into a 50-mL round-bottom flask, were placed1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropan-1-amine(50 mg, 0.154 mmol, 1 equiv.), formaldehyde (10 mg, 0.333 mmol, 2equiv.), DCE (5 mL). The resulting solution was stirred 1 h at 25° C.Sodium triacetoxyborohydride (STAB) (65 mg, 0.307 mmol, 2 equiv.) wasadded to above mixture solution. The resulting solution was stirred 1 hat 25° C. The reaction was monitored by TLC (DCM:MeOH=10:1). Thereaction was then quenched by the addition of water (10 mL) andextracted with DCM and the organic layers combined. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with DCM:MeOH=10:1 to yield1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-N,2-dimethylpropan-1-aminewas obtained as a light yellow solid.

Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₃FN₂O, 339.2 (M+H), found339.2.

Step 2:1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-1-methylurea

Into a 50-mL round-bottom flask, were placed1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-N,2-dimethylpropan-1-amine(30 mg, 0.089 mmol, 1 equiv.), potassium cyanate (36 mg, 0.444 mmol, 5equiv.), AcOH (2 mL), THF (2 mL), H₂O (2 mL). The resulting solution wasstirred overnight at 25° C. The reaction was monitored by TLC(DCM:MeOH=10:1). The mixture was then extracted with ethyl acetate andthe organic layers combined. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withDCM:MeOH=10:1 to yield1-(1-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-2-methylpropyl)-1-methylureawas obtained as a light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₄FN₃O₂, 382.2 (M+H), found382.2.

Step 3:1-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)-1-methylurea

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product asoff white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.49 (s, 1H), 8.10 (d, J=8.8 Hz, 1H),7.87-7.94 (m, 1H), 7.77-7.80 (m, 2H), 7.54-7.60 (m, 1H), 7.29-7.38 (m,1H), 6.85 (d, J=6.8 Hz, 1H), 4.74-4.88 (m, 1H), 2.76 (s, 3H), 2.51-2.55(m, 1H), 1.07 (d, J=6.4 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H). ¹⁹F NMR (400MHz, CD₃OD) δ: −124.40. Mass spectrum (ESI, m/z): Calculated forC₂₁H₂₂FN₃O₂, 368.2 (M+H), found 368.2.

Example 252 Compound #2661-(2-(dimethylamino)ethyl)-3-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)urea

The title compound was prepared according to the procedure described inExample 251 by coulping followed by demethylation with TMSCl/NaI toyield the product as light yellow oil.

¹H NMR (400 MHz, CD₃OD) δ: 8.42 (s, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.85(d, J=8.8 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.54-7.60 (m, 2H), 7.29-7.34(m, 1H), 6.78 (d, J=7.2 Hz, 1H), 4.56 (d, J=7.6 Hz, 1H), 3.42-3.57 (m,2H), 3.22-3.25 (m, 2H), 2.92 (d, J=8.4 Hz, 6H), 2.25-2.34 (m, 1H), 1.02(d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H). ¹⁹F NMR (400 MHz, CD₃OD) δ:−78.55, −124.55. Mass spectrum (ESI, m/z): Calculated for C₂₄H₂₉FN₄O₂,425.2 (M−1.95CF₃COOH+H), found 425.2.

Example 253 Compound #268(E)-2-cyano-1-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)guanidine

Step 1: (Z)-methylN′-cyano-N-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)carbamimidothioate

Into a 50-mL round-bottom flask, were placed3-(1-amino-2-methylpropyl)-6-(8-fluoronaphthalen-2-yl)pyridin-2(1H)-one(80 mg, 0.258 mmol, 1 equiv.), dimethyl cyanocarbonimidodithioate (75mg, 0.513 mmol, 2 equiv.), EtOH (5 mL), TEA (52 mg, 0.514 mmol, 2equiv.). The resulting solution was stirred overnight at 70° C. Thereaction was monitored by LCMS. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withDCM:MeOH=10:1 to yield (Z)-methylN′-cyano-N-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)carbamimidothioateas light yellow oil.

Mass spectrum (ESI, m/z): Calculated for C₂₂H₂₁FN₄OS, 409.1 (M+H), found409.1.

Step 2:(E)-2-cyano-1-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)guanidine

Into a 10-mL sealed tube, were placed (Z)-methylN′-cyano-N-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)carbamimidothioate(50 mg, 0.122 mmol, 1 equiv.), NH₃ in MeOH (3 mL). The resultingsolution was stirred overnight at 70° C. The reaction was monitored byLCMS. The resulting mixture was concentrated under vacuum. The residuewas purified by Prep-HPLC with the following conditions (1#-Waters2767-5): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, Waterof 0.05% TFA and CH₃CN (20% CH₃CN up to 50% in 10 min, up to 100% in 2min, down to 20% in 2 min; Detector, 254 nm to yield(E)-2-cyano-1-(1-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-methylpropyl)guanidinetrifluoroacetic acid as off white solid.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.48 (s, 1H), 8.11 (d, J=8.0 Hz, 1H),7.96-7.97 (m, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.56-7.61 (m, 1H), 7.39-7.44(m, 2H), 7.19 (brs, 1H), 6.75 (brm, 2H), 4.45-4.50 (m, 1H), 2.24-2.28(m, 1H), 0.90 (d, J=6.4 Hz, 3H), 0.82 (d, J=6.4 Hz, 3H). ¹⁹F NMR (400MHz, DMSO-d₆) δ: −73.41, −122.17. Mass spectrum (ESI, m/z): Calculatedfor C_(21.48)H_(20.24)F_(1.72)N₅O_(1.48), 378.2 (M−0.24CH₃COOH+H), found378.2.

Example 254 Compound #230N-(1,3-dihydroxypropan-2-yl)-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-aminopropane-1,3-diol followed bydemethylation with TMSCl/NaI to yield the product as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.37 (s, 1H), 8.01-8.04 (m, 1H), 7.71-7.83(m, 3H), 7.47-7.54 (m, 1H), 7.22-7.28 (m, 1H), 6.79 (d, J=7.2 Hz, 1H),3.84-3.91 (m, 1H), 3.48-3.65 (m, 5H), 2.32-2.40 (m, 1H), 1.06 (d, J=6.6Hz, 3H), 0.83 (d, J=6.6 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −124.43.Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₅FN₂O₄, 413.2 (M+H), found413.1.

Example 255 Compound #231N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 2-amino-2-(hydroxymethyl)propane-1,3-diolfollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (300 MHz, CD₃OD) δ: 8.39 (s, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.82(d, J=8.7 Hz, 1H), 7.71-7.76 (m, 2H), 7.48-7.54 (m, 1H), 7.22-7.28 (m,1H), 6.80 (d, J=7.2 Hz, 1H), 3.63-3.70 (m, 6H), 3.47 (d, J=7.8 Hz, 1H),2.34-2.42 (m, 1H), 1.08 (d, J=5.4 Hz, 3H), 0.83 (d, J=6.6 Hz, 3H). ¹⁹FNMR (300 MHz, CD₃OD) δ: −124.46. Mass spectrum (ESI, m/z): Calculatedfor C₂₄H₂₇FN₂O₅, 443.2 (M+H), found 443.1.

Example 256 Compound #1832-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methyl-N-(tetrahydro-2H-thiopyran-4-yl)butanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with tetrahydro-2H-thiopyran-4-amine followed bydemethylation with TMSCl/NaI to yield the product a white solid.

¹H NMR (400 MHz, CD₃OD) δ: 8.43 (s, 1H), 8.08 (d, J=8.8 Hz, 1H),7.77-7.88 (m, 3H), 7.54-7.59 (m, 1H), 7.28-7.33 (m, 1H), 6.84 (d, J=7.6Hz, 1H), 3.66-3.71 (m, 1H), 3.49 (d, J=10.8 Hz, 1H), 2.63-2.73 (m, 4H),2.35-2.42 (m, 1H), 2.16-2.19 (m, 1H), 2.02-2.06 (m, 1H), 1.57-1.67 (m,2H), 1.08 (d, J=6.4 Hz, 3H), 0.87 (d, J=6.8 Hz, 3H). ¹⁹F NMR (400 MHz,CD₃OD) δ: −124.41.

Mass spectrum (ESI, m/z): Calculated for C₂₅H₂₇FN₂O₂S, 439.2 (M+H),found 439.1.

Example 257 Compound #179N-(1,1-dioxo-1I6-thian-4-yl)-2-[6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl]-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 4-aminotetrahydro-2H-thiopyran 1,1-dioxidefollowed by demethylation with TMSCl/NaI to yield the product as a whitesolid.

¹H NMR (300 MHz, CD₃OD) δ: 8.39 (s, 1H), 8.03 (d, J=9.6 Hz, 1H),7.71-7.83 (m, 3H), 7.47-7.55 (m, 1H), 7.22-7.28 (m, 1H), 6.80 (d, J=7.5Hz, 1H), 3.90-4.01 (m, 1H), 3.48 (d, J=10.8 Hz, 1H), 3.04-3.18 (m, 4 H),2.22-2.37 (m, 2 H), 2.01-2.13 (m, 3 H), 1.04 (d, J=6.6 Hz, 3H), 0.83 (d,J=6.6 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: −77.55, −124.45. Massspectrum (ESI, m/z): Calculated forC_(26.46)H_(27.73)F_(3.19)N₂O_(5.46)S, 471.2 (M−0.73CF₃COOH+H), found471.1.

Example 258 Compound #1782-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methyl-N-(pyrrolidin-3-yl)butanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with tert-butyl 3-aminopyrrolidine-1-carboxylatefollowed by de-Boc protection (i.e. removal of the Boc protecting group)and demethylation with TMSCl/NaI to yield the product as a light pinksolid.

¹H NMR (400 MHz, CD₃OD) δ: 8.38 (s, 1 H), 8.05-8.07 (m, 1 H), 7.75-7.84(m, 3 H), 7.52-7.57 (m, 1 H), 7.26-7.31 (m, 1 H), 6.79-6.85 (m, 1 H),3.47-4.12 (m, 6 H), 2.35-2.58 (m, 2 H), 1.90-2.18 (m, 1 H), 1.08 (d,J=6.4 Hz, 3 H), 0.88 (d, J=8.4 Hz, 3 H). ¹⁹F NMR (400 MHz, CD₃OD) δ:−77.59, −124.62. Mass spectrum (ESI, m/z): Calculated forC_(29.58)H_(28.79)F_(9.37)N₃O_(7.58), 408.2 (M−2.79 CF₃COOH+H), found408.2.

Example 259 Compound #1842-(6-(8-fluoronaphthalen-2-yl)-2-oxo-2,3-dihydropyridin-3-yl)-3-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)butanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 1-(methylsulfonyl)piperidin-4-aminefollowed by demethylation with TMSCl/NaI to yield the product as acolorless oil.

¹H NMR (300 MHz, CD₃OD) δ: 8.40 (s, 1H), 8.03 (d, J=8.7 Hz, 1H),7.79-7.83 (m, 2H), 7.72-7.78 (m, 1H), 7.47-7.55 (m, 1H), 7.22-7.29 (m,1H), 6.89 (d, J=7.5 Hz, 1H), 3.74-3.77 (m, 1H), 3.56-3.63 (m, 2H), 3.46(d, J=10.8 Hz, 1H), 2.84-2.88 (m, 2H), 2.79 (s, 3H), 2.56-2.36 (m, 1H),1.93-1.98 (m, 1H), 1.81-1.86 (m, 1H), 1.47-1.55 (m, 2H), 1.04 (d, J=6.6Hz, 3H), 0.83 (d, J=6.9 Hz, 3H). ¹⁹F NMR (300 MHz, CD₃OD) δ: 0.76.96,−124.42. Mass spectrum (ESI, m/z): Calculated forC_(26.3)H_(30.15)F_(1.45)N₃O_(4.3)S, 500.2[M−0.15CF₃COOH+H], found500.3.

Example 260 Compound #1812-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methyl-N-(1-methyl-1H-benzo[d]imidazol-5-yl)butanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 1-methyl-1H-benzo[d]imidazol-5-aminefollowed by demethylation with TMSCl/NaI to yield the product as a lightyellow solid.

¹H NMR (400 MHz, CD₃OD) δ: 9.30 (s, 1 H), 8.49 (s, 1 H), 8.43 (s, 1 H),8.08 (d, J=8.8 Hz, 1 H), 7.92 (d, J=7.2 Hz, 1 H), 7.86-7.88 (m, 2 H),7.78 (d, J=8.4 Hz, 1 H), 7.67 (d, J=8.8 Hz, 1 H), 7.54-7.59 (m, 1 H),7.28-7.33 (m, 1 H), 6.88 (d, J=7.6 Hz, 1 H), 4.13 (s, 3 H), 3.76 (d,J=10.8 Hz, 1 H), 2.50-2.59 (m, 1 H), 1.17 (d, J=6.4 Hz, 3 H), 0.96 (d,J=6.8 Hz, 3 H). ¹⁹F NMR (400 MHz, CD₃OD) δ: −77.16, −124.43. Massspectrum (ESI, m/z): Calculated forC_(31.82)H_(26.91)F_(6.73)N₄O_(5.82), 469.2 (M−1.91CF₃COOH+H), found469.2.

Example 261 Compound #1802-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methyl-N-(pyridin-4-yl)butanamide

The title compound was prepared according to the procedure described inExample 221 by coulping with 4-aminopyridine followed by demethylationwith TMSCl/NaI to yield the product as a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 8.33-8.38 (m, 3 H), 8.02 (d, J=8.4 Hz, 1 H),7.71-7.84 (m, 3 H), 7.53 (d, J=5.4 Hz, 2 H), 7.46-7.52 (m, 1 H),7.21-7.28 (m, 1 H), 6.81 (d, J=7.5 Hz, 1 H), 3.69 (d, J=10.5 Hz, 1 H),2.41-2.53 (m, 1 H), 1.09 (d, J=6.6 Hz, 3 H), 0.88 (d, J=6.6 Hz, 3 H).¹⁹F NMR (300 MHz, CD₃OD) δ: −124.39. Mass spectrum (ESI, m/z):Calculated for C₂₅H₂₂FN₃O₂, 416.2 (M+H), found 416.1.

Example 262 Compound #2182-hydroxy-3-methyl-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanamide

To5-isopropyl-5-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)oxazolidine-2,4-dione(prepared according to JIN, J., et al., “Novel3-Oxazolidinedione-6-aryl-pyridinones as Potent, Selective, and OrallyActive EP ₃ Receptor Antagonists”, ACS Med. Chem. Lett., 2010, pp316-320, Vol. 1) (200 mg, 0.551 mmol, 1 equiv.) in mixed solvent of THF(2 mL) and water (2 mL) was added NaOH (66 mg, 1.656 mmol, 3 equiv.) atroom temperature. The result solution was heated to reflux for 6 hours.The solvent was neutralized with 1 N HCl. The solvent was removed andthe residue was partitioned between ethyl acetate and water. The organiclayer was washed with water and brine, dried over anhydrous Na₂SO₄,filtered and concentrated and purified by silica gel column to yield thetitle product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 12.2 (br, s, 1H), 8.31 (d, J=7.5 Hz, 1 H),8.25 (s, 1H), 8.08 (m, 2H), 7.98 (m, 1H), 7.72 (d, J=7.0 Hz, 1H), 7.61(m, 2H), 7.02 (d, J=7.5 Hz, 1H), 6.21 (br, s, 1H), 2.95 (m, 1H), 0.95(d, J=7.0 Hz, 3H), 0.85 (d, J=7.0 Hz, 3H). Mass spectrum (ESI, m/z):Calculated for C₂₀H₂₀N₂O₃, 337.39 (M+H), found 337.5.

Example 263 Compound #2172-fluoro-3-methyl-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanamide

The title compound was prepared according to the procedure described inExample 165 by fluorination of2-hydroxy-3-methyl-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanamidewith DAST to yield the product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.21 (d, J=5.5 Hz, 1 H), 8.02 (m, 2H), 7.95(m, 2H), 7.72 (d, J=7.0 Hz, 1H), 7.61 (d, J=5.8 Hz, 2H), 6.90 (d, J=5.1Hz, 1H), 5.55 (br, s, 1H), 3.10 (m, 1H), 1.01 (d, J=7.0 Hz, 3H), 0.85(d, J=7.0 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₂H₁₉FN₂O₂,339.38 (M+H), found 339.5.

Example 264 Compound #2162-fluoro-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 165 by fluorination of2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-hydroxy-3-methylbutanamidewith DAST to yield the product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 12.7 (s, br, 1H), 8.51 (s, 1H), 8.05 (m, 1H),7.92 (d, J=7.0 Hz, 1H), 7.78 (d, J=7.2 Hz, 1H), 7.72 (dd, J=7.5, 4.5 Hz,1H), 7.52 (m, 1H), 7.26 (m, 1H), 6.81 (d, J=7.2 Hz, 1H), 5.42 (br, s,1H), 3.02 (m, J=10.5, 1H), 0.90 (d, J=5.6 Hz, 3H), 0.75 (d, J=5.5 Hz,3H). Mass spectrum (ESI, m/z): Calculated for C₂₀H₁₈F₂N₂O₂, 357.37(M+H), found 357.4.

Example 265 Compound #2242-fluoro-3-methyl-N-(methylsulfonyl)-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanamide

The title compound was prepared according to the procedure described inExample 171 by reacting2-fluoro-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide with MsCl to yield the product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.18 (s, 1H), 8.05 (d, J=7.5 Hz, 1 H), 7.95(d, J=8.5 Hz, 2H), 7.92 (m, 1H), 7.68 (d, J=6.5 Hz, 1H), 7.62 (d, J=7.0Hz, 2H), 6.91 (d, J=6.1 Hz, 1H), 3.10 (m, 1H), 1.02 (d, J=6.0 Hz, 3H),0.82 (d, J=6.5 Hz, 3H). Mass spectrum (ESI, m/z): Calculated forC₂₁H₂₁FN₂O₄S, 417.47 (M+H), found 417.5.

Example 266 Compound #173N-((3,5-difluorophenyl)sulfonyl)-2-fluoro-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide

The title compound was prepared according to the procedure described inExample 171 by reacting2-fluoro-2-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-methylbutanamide with 3,5-di-fluoro-phenyl-sulfonylchloride to yield theproduct as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 12.5 (s, br, 1H), 8.48 (s, 1H), 8.02 (m, 1H),7.89 (d, J=6.0 Hz, 1H), 7.73 (d, J=7.0 Hz, 1H), 7.65 (d, J=7.5 Hz, 1H),7.56 (m, 2H), 7.52 (m, 1H), 7.26 (m, 1H), 7.03 (m, 1H), 6.81 (d, J=7.2Hz, 1H), 3.10 (m, J=9.5, 1H), 0.95 (d, J=5.6 Hz, 3H), 0.81 (d, J=5.5 Hz,3H). Mass spectrum (ESI, m/z): Calculated for C₂₆H₂₀F₄N₂O₄S, 533.51(M+H), found 533.8.

Example 267 Compound #2252-hydroxy-3-methyl-2-(6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-oxo-1,2-dihydropyridin-3-yl)butanamide

The title compound was prepared according to the procedure described inExample 262 by ring-opening of5-isopropyl-5-(6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-oxo-1,2-dihydropyridin-3-yl)oxazolidine-2,4-dionewith NaOH to yield the product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.01 (s, 1H), 7.92 (d, J=5.6 Hz, 1 H), 7.72(d, J=6.5 Hz, 1H), 7.58 (m, 1H), 6.97 (d, J=7.0 Hz, 1H), 6.10 (s, br,1H), 3.95 (s, 3H), 3.42 (m, 2H), 3.35 (m, 2H), 3.05 (m, 1H), 1.10 (m,3H), 0.92 (m, 3H). Mass spectrum (ESI, m/z): Calculated for C₁₉H₂₃N₃O₄,358.41 (M+H), found 358.2.

Example 268 Compound #2553-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-hydroxy-4-methylpentanamide

Step 1:3-(6-(8-fluoronaphthalen-2-yl)-2-methoxypyridin-3-yl)-3-hydroxy-4-methylpentanamide

Trimethylsilyl N-(trimethylsilyl)acetimidate (314 mg, 1.546 mmol, 1equiv.) in THF (5 mL) was treated with n-BuLi (2.5 N, 618 μL, 1.546mmol, 1 equiv.) dropwise at −78° C. for 5 min and the reaction wasstirred for another 30 min at −78° C. Then2-(8-fluoronaphthalen-2-yl)-6-methoxypyridine (500 mg, 1.546 mmol, 1equiv.) in THF (1 mL) was dropwise added into the reaction and stirredfor another 2 hours. The reaction was warmed to room temperature andquenched with saturated ammonium chloride. The solvent was removed andthe residue was partitioned between ethyl acetate and water. The organiclayer was washed with brined, dried and concentrated and purified bysilica gel column using 10˜50% ethyl acetate/heptanes to yield the titleproduct as a colorless oil.

Step 2:3-(6-(8-fluoronaphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-hydroxy-4-methylpentanamide

The title compound was prepared according to the procedure described inExample 1 step 5 by demethylation with TMSCl/NaI to yield the product asa white solid.

¹H NMR (400 MHz, CDCl₃) δ: 11.9 (br, s, 1H), 8.01 (d, J=5.5 Hz, 1 H),7.81 (d, J=6.5 Hz, 1H), 7.70 (m, 2H), 7.52 (m, 1H), 7.24 (m, 2H), 6.75(d, J=7.1 Hz, 1H), 6.45 (br, s, 1H), 3.01 (m, 1H), 2.72 (abq, J=9.5 Hz,1H0, 2.38 (abq, J=9.0 Hz, 1H), 1.21 (d, J=7.0 Hz, 3H), 0.88 (d, J=7.0Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C₂₁H₂₁FN₂O₃, 369.41(M+H), found 369.7.

Example 269 Compound #2262-(cyclohex-1-en-1-yl)-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetamide

The title compound was prepared according to the procedure described inExample 219 by hydrolysis, aminolysis of ethyl2-(cyclohex-1-en-1-yl)-2-(6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetateto yield the product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.25 (s, 1H), 8.05 (d, J=6.5 Hz, 1 H), 7.95(m, 3 H), 7.72 (d, J=7.0 Hz, 1H), 7.62 (m, 2H), 6.95 (d, J=6.5 Hz, 1H),6.10 (s, br, 1H), 5.85 (s, 1H), 4.55 (s, 1H), 2.10 (m, 2H), 2.02 (m,2H), 1.75 (m, 4H). Mass spectrum (ESI, m/z): Calculated for C₂₃H₂₂N₂O₂,359.44 (M+H), found 359.2.

BIOLOGICAL EXAMPLES Biological Example 1 [3H]-PGE2 Binding Assay

EP3 competition binding was determined using the following materials andexperimental conditions:

Beads = Perkin Elmer RPNQ0001 [3H]PGE2 = Perkin Elmer NET428025UC384-well plate = Perkin Elmer 6007290 EP3 membrane = Millipore HTS092MMembrane concentration = 2 μg/well Beads concentration = 0.25 mg/well[3H]-PGE2 = 2 nM; DMSO - 0.1% Binding buffer = 50 mM Tris, 10 mM MgCl₂,1 mM EDTA, PH 7.4.

The reaction system was prepared by mixing 5 μl of unlabeled compound; 5μl of diluted [3H]-PGE2; 5 μl of diluted membrane; and 15 μl of SPAbeads dissolved in binding buffer (adding in the following sequence:Unlabeled compound, [3H]-PGE2, Membrane and Beads).

Procedure:

The binding buffer was removed from refrigeration (@ 4° C.) and allowedto warm to room temperature. Test compound (@ stock concentration of 10nM in DMSO) was serial dilutes (1:3) with 100% DMSO using Echo plate.Diluted test compound (30 nL) was dispensed to the 384-well assay plate(using Echo 550 Labcyte System). To each well was then added assaybuffer (5 μl) and each well was spun. Beads were weighed out, dissolvedin assay buffer to a concentration of 0.25 mg/15 μl. Original membranewas diluted with assay buffer to a concentration of 2 μg/5 μl. Original[3H]-PGE2 with diluted with assay buffer to a concentration of 12 nM. Toeach test well were then added diluted [3H]-PGE2 (5 μl), dilutedmembrane (5 μl), and dissolved beads (15 μl). The plate was equilibratedat room temperature on a plate shaker for 2 hours and then read with aTOPCOUNT scintillation plate reader. Results were analyzed using a Prismprogram with non-linear regression, one-site fit for Ki.

Biological Example 2 CHO Cell cAMP Assay

This assay monitored the cAMP generation in CHO cells over-expressingthe EP3 receptor in the presence or absence of antagonist stimulatedwith Forskolin (FSK, CAS No. 66428-89-5) and a known EP3 Agonist(sulprostone, CAS No. 60325-46-4). For detection, a homogeneouscompetitive immunoassay (Time Resolved Fluorescence Energy Transfer(hTR-FRET)) was used.

Cells (6K cells per well) were plated in Poly-D-Lysine coated plates theday before the assay was to be run and were incubated at 37° C. One hourbefore the assay the media was removed and replaced with assay buffer(500 mL HBSS (+Ca)+2.5 mL 1M HEPES+6.66 mL 7.5% BSA) (starved at 37°C.). At the start of the assay the buffer was removed from the cells andreplaced with buffer containing test compound(s). Sulprostone at an EC₈₀dose (700 nM) and FSK at an EC₇₀ dose (2 μM) were added to initiate thereaction (37° C. for 30 minutes).

FSK increases cAMP production and sulprostone decreases cAMP productionproduced by FSK. In this assay, EP3 antagonists will increase the cAMPto the level of cAMP generated by FSK alone.

The reaction was terminated with the addition of cAMP detection reagents(labeled cAMP and labeled cAMP antibody in lysis buffer (HTRF reagent,which utilizes a cryptate-labeled anti-cAMP and d2-labeled cAMP-d2 is anHTRF acceptor fluorophore)). Approximately one hour later the plateswere read on an Envision (Perkin Elmer) in HTRF mode. Well results werecalculated based on a ratio of counts at 665 nm and 615 nm (data outputwas a calculation of the ratio: (read @665 nm/read @ 615 nm)*1000. Fortest compounds dosed serially, well results were converted to nM cAMPusing a cAMP standard run on each plate. nM cAMP from a set of wellsdosed with test compound(s) were plotted. nM cAMP was calculated foreach well from a standard curve located on each plate (P1-12 and P13-24)by first calculating the slope and deriving the intercept (b):

$m = \frac{\Delta\;{NS}_{{cAMP}\;\_\;{standard}\;\_\;{curve}}}{{\Delta\lbrack{standard\_ curve}\rbrack}_{\backslash}}$NS_(cAMP _ standard _ curve) = m(nM  cAMP_standard_curve) + b

NS_(P), NS_(N), NS_(sample) were converted to nM cAMP using thefollowing equation:

${nM\_ cAMP} = \frac{{NS} - b}{m}$

IC₅₀ values were determined from a 4-point fit (Hill equation) of asingle 11-point compound dosing. A best-fit curve was determined by theminimum sum of squares method plotting cAMP produced vs compoundconcentration.

Representative compounds of the present invention (including compoundsof formula (I), compounds of formula (II) and compounds of formula(III)) were tested according to the procedures as described inBiological Example 1 and Biological Example 2 above, with results aslisted in Table BIO-1 below. A notation of “NT” indicates that thecompound was Not Tested in the assay listed.

TABLE BIO-1 Biological Assay Results ID [3H]-PGE2 CHO_cAMP NO. BindingKi (μM) IC₅₀ (μM) 1 0.039 0.088 2 0.038 0.057 3 0.017 0.349 4 0.0881.800 5 0.017 0.293 6 0.013 0.061 7 0.039 0.149 8 0.050 0.066 9 0.0230.108 10 0.028 NT 11 0.028 0.055 12 1.346 >20 13 0.003 0.022 14 >10 >2015 0.007 NT 16 0.006 0.017 17 0.014 NT 18 2.639 >20 19 0.121 NT 20 0.011NT 21 0.034 0.849 22 0.097 0.204 23 0.228 NT 24 0.054 NT 25 >10 NT 260.328 NT 27 0.039 NT 28 5.623 >20 29 0.003 0.009 30 0.002 0.012 31 0.0370.482 32 0.292 NT 33 0.735 NT 34 0.267 17.595 35 0.024 0.215 36 0.195 NT37 0.024 NT 38 0.013 NT 39 0.089 NT 40 0.011 0.044 41 0.002 NT 42 0.0090.020 43 5.668 >20 44 0.093 0.505 45 0.059 NT 46 0.452 NT 47 0.025 NT 480.002 NT 49 0.017 0.091 50 1.083 NT 51 2.058 NT 52 0.019 NT 53 0.006 NT54 0.121 NT 55 0.003 0.033 56 0.020 0.230 57 0.006 NT 58 0.007 NT 590.085 0.611 60 0.027 0.092 61 0.043 0.376 62 0.009 0.021 63 0.013 0.02764 0.008 0.009 65 0.006 0.017 66 0.004 0.014 67 0.007 0.050 68 0.0160.039 69 0.046 0.323 70 0.034 0.134 71 0.025 0.112 72 0.034 0.070 730.017 0.065 74 0.008 0.027 75 0.023 0.092 76 0.007 0.033 77 0.016 0.06078 0.011 0.010 79 0.007 0.009 80 0.006 0.011 81 0.006 0.015 82 0.0230.137 83 NT NT 84 0.007 0.026 85 0.044 0.122 86 0.114 0.916 87 0.0320.149 88 NT NT 89 0.010 0.031 90 0.633 5.434 91 >10 >20 92 0.009 0.00793 1.067 9.940 94 0.020 0.181 95 0.015 0.041 96 0.017 0.039 97 0.1790.666 98 >10 >20 99 0.921 4.881 100 0.028 0.102 101 0.015 0.120 102 NTNT 103 0.022 0.033 104 0.053 0.375 105 0.013 0.023 106 0.050 0.555107 >10 >20 108 0.171 0.602 109 0.027 0.115 110 >10 >20 111 0.162 0.585112 0.057 0.212 113 NT NT 114 NT NT 115 0.002 0.011 116 0.008 0.076 1170.033 0.205 118 0.044 0.131 119 0.009 0.068 120 >10 >20 121 0.073 0.363122 0.032 0.278 123 0.023 0.185 124 0.202 19.187 125 0.487 0.658 1260.065 0.382 127 0.046 0.548 128 0.154 18.001 129 0.006 0.149 130 0.0120.072 131 0.012 0.036 132 0.050 0.310 133 0.012 0.235 134 0.004 0.008135 0.085 NT 136 0.379 0.367 137 0.054 0.218 138 0.012 0.021 139 0.0100.017 140 0.011 0.076 141 0.025 NT 142 0.121 NT 143 0.308 0.734 1440.007 NT 145 0.001 0.002 146 0.006 NT 147 0.632 NT 148 0.787 NT 1490.002 0.009 150 0.005 0.008 151 0.011 NT 152 0.428 2.138 153 0.043 0.400154 0.009 0.028 155 0.005 0.020 156 0.057 0.508 157 0.024 0.064 1580.009 0.010 159 0.022 0.185 160 0.013 0.044 161 0.027 0.095 162 0.0130.117 163 0.014 0.122 164 0.026 0.485 165 0.031 0.250 166 0.006 0.040167 0.151 0.779 168 0.026 0.130 169 0.051 0.476 170 0.023 0.038 1710.029 NT 172 0.025 NT 173 0.153 1.304 174 0.002 0.003 175 0.110 0.171176 0.028 0.067 177 0.014 0.347 178 0.020 0.220 179 0.003 0.006 1800.006 0.024 181 0.004 0.006 182 0.041 0.638 183 0.003 0.001 184 0.0020.002 185 0.031 0.314 186 0.040 2.825 187 >10 >20 188 0.015 0.120 1890.016 0.109 190 0.032 0.614 191 0.005 0.020 192 0.060 1.327 194 >10 >20195 0.042 0.286 196 0.008 0.087 197 0.169 0.967 198 0.019 0.530199 >10 >20 200 0.038 1.249 201 0.010 0.013 203 0.106 1.415 204 0.012 NT205 0.051 NT 206 0.025 NT 207 0.015 NT 208 0.158 NT 209 0.020 NT 2100.042 NT 211 0.005 0.037 213 0.007 0.281 214 >10 >20 215 0.165 NT 2160.026 0.426 217 0.049 1.138 218 0.050 0.509 219 0.108 4.069 220 0.0180.191 221 0.051 0.243 222 0.327 4.271 223 0.496 3.579 224 1.290 10.755225 0.343 4.574 226 0.186 4.957 227 0.033 0.445 228 0.003 0.010 2290.012 0.142 230 0.010 0.041 231 0.025 0.099 232 0.125 1.635 233 0.0150.325 234 0.004 0.023 236 0.002 0.006 237 0.004 0.012 238 0.005 0.012239 0.001 0.002 241 0.637 9.629 242 0.398 3.957 243 2.595 14.031 2440.501 2.393 246 >10 17.041 247 0.771 2.400 248 0.010 NT 249 0.005 0.053250 0.069 0.931 251 0.003 0.005 252 0.180 0.499 253 0.012 0.059 2540.344 2.742 255 0.009 0.115 256 0.164 0.579 257 0.002 0.023 258 0.0080.136 259 0.028 0.242 260 0.006 0.015 261 0.020 0.024 262 0.152 0.282263 0.108 0.336 264 0.050 0.310 265 0.034 0.249 266 0.028 0.736 2670.006 0.014 268 0.006 0.017 270 0.164 0.540 271 0.006 NT 272 >10 >20 2730.027 0.067 274 >10 >20 275 6.14 >20 276 5.65 7.60 277 0.107 0.548 2780.368 0.591 279 0.060 NT 280 0.076 0.671 281 0.037 0.527 282 0.740 0.900283 0.049 0.180 285 0.035 0.164 286 0.064 0.179 287 0.157 8.68 288 0.1800.656 289 1.80 >20 290 0.116 1.912 291 0.003 0.019 292 0.002 0.006 2930.014 0.207 294 0.006 0.056 295 0.002 0.079 296 0.001 0.103 297 0.0080.194 298 0.979 8.30 299 0.029 NT 300 0.005 NT 302 NT NT 303 0.014 1.284304 0.270 0.680 305 0.022 0.063 306 0.054 0.111 307 0.053 0.385 3080.046 0.210 309 0.012 0.066 310 0.071 NT

Biological Example 3 IV Infused EP3 Antagonists on Circulating Insulinand Glucose in the Sulprostone Infusion IVGTT Model

Jugular vein and carotid artery cannulated male Sprague Dawley rats(˜250 g, available from Charles River) were housed one rat per suspendedcage in a temperature-controlled room with 12-hour light/dark cycle. Therats were allowed ad libitum access to water and maintained on a regulardiet. Animals were acclimated for minimum 5 days prior to the start ofthe experiment. Experimental procedures were carried out in accordancewith institutional standards for animal care and were approved by theinstitute's animal care and use committee.

A blood sample for insulin and blood chemistry was collected at 20 min(t=−20) prior to the start of dosing with sulprostone and/or testcompound (EP3 antagonist). Sulprostone solution was prepared in 10 U/mlheparin saline solution at a concentration of 0.09 mg/ml. Test compoundsolution was prepared in 20% HPBCD (pH=7) at a concentration of 0.048mg/ml (1×K_(i)), 0.336 mg/ml (7×k_(i)) and 0.480 mg/ml (10×K_(i)). Finaltest compound solution was mixed 1:1 volume with sulprostone solutionimmediately prior to starting the experiment. Tested compound solution(at 0.096 mpk, 0.671 mpk or 0.959 mpk (mg/kg)) or saline bolus at 2ml/kg was injected into the animals and a blood sample was taken forexposure analysis at 2 min after the bolus. After 18 min, another bloodsample was taken for exposure analysis and also for measurement ofinsulin and blood chemistry (t=0). Animals were then injected (throughinfusion syringe) with a 50% glucose solution (1 g/kg) followed by IVinfusion at 2 ml/kg/h with the vehicle (20% HPBCD, pH=7), 3 μg/kg/minsulprostone only or a mixture of 3 μg/kg/min sulprostone and the testcompound at 0.0268 mpk/h, 0.188 mpk/h and 0.268 mpk/h. Blood sampleswere then collected at 2, 5, 10, 15, 20, 30 min post infusion formeasurement of insulin and blood chemistry. Another blood sample wascollected at 31 min post infusion for exposure analysis.

Blood samples from all animals were collected into Heparin treatedtubes. Background was measured via a glucometer at the 0 and 2 min timepoints to ensure that the animal received the glucose bolus. Plasmainsulin was measured via a Meso Scale Discovery metabolic assay(available from Meso Scale). Plasma glucose, free fatty acid (FFA),triglycerides, cholesterol and ketones were measured on an OLYMPUSAU400E chemistry analyzer. Observations on animal health were recordedthroughout the procedure. Samples from time points (after the bolus) 2,20 and 50 min were submitted for measurement of exposure by plasma drugconcentration.

Statistical analysis was performed using the program Prism (Graphpad,Monrovia, Calif.) with either a repeated measures 2-way ANOVA (glucoseand insulin curves with Bonferroni's multiple comparison test) or aone-way ANOVA and Tukey's multiple comparison test (AUC). AUC=Integratedarea under the stimulated glucose excursion and insulin curve from t=0to t=30 minutes and from t=0 to t=10 min. AIR is calculated as the meaninsulin at 2, 5 and 10 min after glucose bolus—baseline.

Testing according to the procedure describe above, Compound #62,prepared for example as described in Example 5 was shown to reversesuppression of glucose stimulate insulin secretion (GSIS) by sulprostoneat 7×K_(i) and 10×K_(i) (targeted, mEP3 K_(i)=8.6 nM) in SD rats.

Formulation Example 1 Solid, Oral Dosage Form—Prophetic Example

As a specific embodiment of an oral composition, 100 mg of, for exampleCompound #62 prepared as in Example 5, is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size O hard gel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

Throughout this application, various publications are cited. Thedisclosure of these publications is hereby incorporated by referenceinto this application to describe more fully the state of the art towhich this invention pertains.

What is claimed:
 1. A compound of formula (III)

wherein

 is selected from the group consisting of naphth-2-yl, indol-5-yl,indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl,benzothiazol-5-yl, benzothiazol-6-yl, benzoisothiazol-6-yl,chroman-7-yl, chromen-7-yl, benzo[d][1,3]dioxol-5-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl and2,3-dihydro-benzo[b][1,4]dioxin-6-yl; wherein the naphth-2-yl,indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl,benzimidazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl,benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl,benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl is optionally substituted on thephenyl portion of the

 bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, cyano, C₁₋₃alkyl, fluorinatedC₁₋₂alkyl, C₁₋₃alkoxy, fluorinated C₁₋₂alkoxy and C₃₋₆cycloalkyl; andwherein the naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl,benzimidazol-5-yl, benzimidazol-6-yl, benzothiazol-5-yl,benzothiazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl,benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl; is further optionally substitutedon the

 portion of the

 bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, cyano, C₁₋₃alkyl, fluorinatedC₁₋₂alkyl, C₁₋₃alkoxy, fluorinated C₁₋₂alkoxy and C₃₋₆cycloalkyl; R⁶ isselected from the group consisting of hydrogen, halogen and C₁₋₄alkyl;R⁷ is selected from the group consisting of hydrogen, halogen andC₁₋₄alkyl; Y is selected from the group consisting of —CR^(H)R^(J)— and—CR^(H)R^(J)—CHR^(K)—; wherein R^(H) and R^(J) are each independentlyselected from the group consisting of hydrogen, halogen, hydroxy,C₁₋₄alkyl, fluorinated C₁₋₂alkyl, C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl,phenyl, benzyl and phenyl-ethyl-; provided that when one of R^(H) orR^(J) is C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, phenyl, benzyl orphenylethyl-, then the other of R^(H) or R^(J) is hydrogen; and whereinR^(K) is selected from the group consisting of hydrogen and C₁₋₄alkyl;alternatively, when Y is —CR^(H)R^(J)—, then R^(H) and R^(J) may betaken together with the carbon atom to which they are bound to formC₃₋₆cycloalkyl; Z is selected from the group consisting of—C(O)—NR^(L)R^(M), —C(O)—NH—OR^(N), —C(O)—NH—SO₂—R^(N);—C(O)—NH(CH(CH₂OH)₂), —C(O)—NH(C(CH₂OH)₃), —C(O)—NH—(CH₂CH₂O)_(a)—R^(N),—C(O)—NH—CH(CH₂O—(CH₂CH₂O)_(b)—R^(N))₂,—C(O)—NH—C(CH₂O—(CH₂CH₂O)_(b)—R^(N))₃), —C(O)—NH—CH₂CH₂—NR^(P)R^(Q),—C(O)—NH—(CH₂CH₂O)_(a)—CH₂CH₂—NR^(P)R^(Q), —NR^(S)—C(O)—NR^(P)R^(Q),—NR^(S)—C(O)—NH—CH₂CH₂—NR^(P)R^(Q) and —NR^(S)—C(NH₂)═N—CN; wherein a isan integer from 1 to 6; wherein b is an integer from 0 to 3; whereinR^(L) and R^(M) are each independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; wherein R^(N) is selected from thegroup consisting of hydrogen and C₁₋₂alkyl; wherein R^(P) and R^(Q) areeach independently selected from the group consisting of hydrogen andC₁₋₂alkyl; and wherein R^(S) is selected from the group consisting ofhydrogen and C₁₋₂alkyl; or a tautomer or a pharmaceutically acceptablesalt thereof.
 2. A compound as in claim 1, wherein

is selected from the group consisting of naphth-2-yl, indol-5-yl,indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl,benzothiazol-5-yl, benzothiazol-6-yl, benzoisothiazol-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl and2,3-dihydro-benzo[b][1,4]dioxin-6-yl; wherein the naphth-2-yl,indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl,benzimidazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl,benzoisothiazol-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl is optionally substituted on thephenyl portion of the

 bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, C₁₋₃alkyl, fluorinated C₁₋₂alkyl,C₁₋₃alkoxy and fluorinated C₁₋₂alkoxy; and wherein the naphth-2-yl,indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl,benzimidazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl,benzoisothiazol-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or2,3-dihydro-benzo[b][1,4]dioxin-6-yl is further optionally substitutedon the

 portion of the

 bicycle with one to two substituents independently selected from thegroup consisting of halogen, oxo, C₁₋₃alkyl, fluorinated C₁₋₂alkyl,C₁₋₃alkoxy and fluorinated C₁₋₂alkoxy; R⁶ is selected from the groupconsisting of hydrogen, fluoro and C₁₋₂alkyl; R⁷ is selected from thegroup consisting of hydrogen, fluoro and C₁₋₂alkyl; Y is selected fromthe group consisting of —CR^(H)R^(J)— and —CR^(H)R^(J)—CHR^(K)—; whereinR^(H) and R^(J) are each independently selected from the groupconsisting of hydrogen, halogen, hydroxy, C₁₋₄alkyl, fluorinatedC₁₋₂alkyl, C₃₋₆cycloalkyl and C₅₋₆cycloalkenyl; provided that when oneof R^(H) or R^(J) is C₃₋₆cycloalkyl or C₅₋₆cycloalkenyl, then the otherof R^(H) or R^(J) is hydrogen; and wherein R^(K) is selected from thegroup consisting of hydrogen and C₁₋₄alkyl; alternatively, when Y is—CR^(H)R^(J)—, then R^(H) and R^(J) may be taken together with thecarbon atom to which they are bound to form C₅₋₆cycloalkyl; Z isselected from the group consisting of —C(O)—NR^(L)R^(M),—C(O)—NH—OR^(N), —C(O)—NH—SO₂—R^(N); —C(O)—NH(CH(CH₂OH)₂),—C(O)—NH(C(CH₂OH)₃), —C(O)—NH—(CH₂CH₂O)_(a)—R^(N),—C(O)—NH—CH(CH₂O—(CH₂CH₂O)_(b)—R^(N))₂,—C(O)—NH—C(CH₂O—(CH₂CH₂O)_(b)—R^(N))₃), —C(O)—NH—CH₂CH₂—NR^(P)R^(Q),—C(O)—NH—(CH₂CH₂O)_(a)—CH₂CH₂—NR^(P)R^(Q), —NR^(S)—C(O)—NR^(P)R^(Q),—NR^(S)—C(O)—NH—CH₂CH₂—NR^(P)R^(Q) and —NR^(S)—C(NH₂)═N—CN; wherein a isan integer from 1 to 4; wherein b is an integer from 0 to 3; whereinR^(L) and R^(M) are each independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; wherein R^(N) is selected from thegroup consisting of hydrogen and C₁₋₂alkyl; wherein R^(P) and R^(Q) areeach independently selected from the group consisting of hydrogen andC₁₋₂alkyl; and wherein R^(S) is selected from the group consisting ofhydrogen and C₁₋₂alkyl; or a tautomer or a pharmaceutically acceptablesalt thereof.
 3. A compound as in claim 2, wherein

is selected from the group consisting of naphth-2-yl, benzothiazol-5-yl,benzothiazol-6-yl, 3,4-dihydro-benzo[b][1,4]oxazin-6-yl and3,4-dihydro-benzo[b][1,4]oxazin-7-yl; wherein the naphth-2-yl,benzothiazol-5-yl, benzothiazol-6-yl,3,4-dihydro-benzo[b][1,4]oxazin-6-yl or3,4-dihydro-benzo[b][1,4]oxazin-7-yl is optionally substituted on thephenyl or

 portion of the

 with a substituent selected from the group consisting of halogen,C₁₋₃alkyl and C₁₋₂alkoxy; R⁶ is hydrogen; R⁷ is hydrogen; Y is selectedfrom the group consisting of —CR^(H)R^(J)— and —CR^(H)R^(J)—CHR^(K)—;wherein R^(H) and R^(J) are each independently selected from the groupconsisting of hydrogen, halogen, hydroxy, C₁₋₄alkyl andC₅₋₆cycloalkenyl; provided that when one of R^(H) or R^(J) isC₅₋₆cycloalkenyl, then the other of R^(H) or R^(J) is hydrogen; andwherein R^(K) is selected from the group consisting of hydrogen andC₁₋₄alkyl; Z is selected from the group consisting of —C(O)—NR^(L)R^(M),—C(O)—NH—OR^(N), —C(O)—NH—SO₂—R^(N); —C(O)—NH(CH(CH₂OH)₂),—C(O)—NH(C(CH₂OH)₃), —C(O)—NH—(CH₂CH₂O)_(a)—R^(N),—C(O)—NH—CH₂CH₂—NR^(P)R^(Q), —C(O)—NH—(CH₂CH₂O)_(a)—CH₂CH₂—NR^(P)R^(Q),—NR^(S)—C(O)—NR^(P)R^(Q), —NR^(S)—C(O)—NH—CH₂CH₂—NR^(P)R^(Q) and—NR^(S)—C(NH₂)═N—CN; wherein a is an integer from 1 to 3; wherein R^(L)and R^(M) are each independently selected from the group consisting ofhydrogen and C₁₋₄alkyl; wherein R^(N) is selected from the groupconsisting of hydrogen and methyl; wherein R^(P) and R^(Q) are eachindependently selected from the group consisting of hydrogen and methyl;and wherein R^(S) is selected from the group consisting of hydrogen andmethyl; or a tautomer or a pharmaceutically acceptable salt thereof. 4.A compound as in claim 3, wherein

is selected from the group consisting of naphth-2-yl,6-fluoro-naphth-2-yl, 8-fluoro-naphth-2-yl, 6-methoxy-naphth-2-yl,benzothiazol-5-yl, benzothiazol-6-yl,4-methyl-3,4-dihydro-benzo[b][1,4]oxazin-6-yl and4-methyl-3,4-dihydro-benzo[b][1,4]oxazin-7-yl; R⁶ is hydrogen; R⁷ ishydrogen; Y is selected from the group consisting of —CH(isopropyl),—C(OH)(isopropyl)-, —C(F)(isopropyl)-, —C(methyl)(isopropyl)-,—CH(cyclohex-1-en-1-yl), —CH(isopropyl)-CH₂— and —CH₂—CH(isopropyl)-; Zis selected from the group consisting of —C(O)—NH₂, —C(O)—NH(isopropyl),—C(O)—NH(OCH₃), —C(O)—NH(CH(CH₂OH)₂), —C(O)—NH(C(CH₂OH)₃),—C(O)—NH—CH₂CH₂—N(CH₃)₂, —C(O)—NH—CH₂CH₂OH,—C(O)—NH—CH₂CH₂O—CH₂CH₂—N(CH₃)₂,—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂—N(CH₃)₂,—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂O—CH₃, —C(O)—NH—SO₂—CH₃, —NH—C(O)—NH₂,—N(CH₃)—C(O)—NH₂, —NH—C(O)—NH—CH₂CH₂—N(CH₃)₂ and —NH-(E)-C(NH₂)═N—CN; ora tautomer or a pharmaceutically acceptable salt thereof.
 5. A compoundas in claim 4, wherein

is selected from the group consisting of naphth-2-yl and8-fluoro-naphth-2-yl; R⁶ is hydrogen; R⁷ is hydrogen; Y is selected fromthe group consisting of —CH(isopropyl), —C(OH)(isopropyl)-,—C(F)(isopropyl)-, —C(methyl)(isopropyl)-, —CH(cyclohex-1-en-1-yl),—CH(isopropyl)-CH₂— and —CH₂—CH(isopropyl)-; Z is selected from thegroup consisting of —C(O)—NH₂, —C(O)—NH(isopropyl), —C(O)—NH(OCH₃),—C(O)—NH(CH(CH₂OH)₂), —C(O)—NH(C(CH₂OH)₃), —C(O)—NH—CH₂CH₂—N(CH₃)₂,—C(O)—NH—CH₂CH₂OH, —C(O)—NH—CH₂CH₂O—CH₂CH₂—N(CH₃)₂,—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂—N(CH₃)₂,—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂O—CH₃, —C(O)—NH—SO₂—CH₃, —NH—C(O)—NH₂,—N(CH₃)—C(O)—NH₂, —NH—C(O)—NH—CH₂CH₂—N(CH₃)₂ and —NH-(E)-C(NH₂)═N—CN; ora tautomer or a pharmaceutically acceptable salt thereof.
 6. A compoundas in claim 4, wherein

is selected from the group consisting of naphth-2-yl and8-fluoro-naphth-2-yl; R⁶ is hydrogen; R⁷ is hydrogen; Y is selected fromthe group consisting of —CH(isopropyl), —C(OH)(isopropyl)-,—C(F)(isopropyl)-, —CH(isopropyl)-CH₂— and —CH₂—CH(isopropyl)-; Z isselected from the group consisting of —C(O)—NH₂, —C(O)—NH(isopropyl),—C(O)—NH(OCH₃), —C(O)—NH(CH(CH₂OH)₂), —C(O)—NH(C(CH₂OH)₃),—C(O)—NH—CH₂CH₂—N(CH₃)₂, —C(O)—NH—CH₂CH₂OH,—C(O)—NH—CH₂CH₂O—CH₂CH₂—N(CH₃)₂,—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂—N(CH₃)₂,—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂O—CH₃, —C(O)—NH—SO₂—CH₃, —NH—C(O)—NH₂,—N(CH₃)—C(O)—NH₂, —NH—C(O)—NH—CH₂CH₂—N(CH₃)₂ and —NH-(E)-C(NH₂)═N—CN; ora tautomer or a pharmaceutically acceptable salt thereof.
 7. A compoundas in claim 4, wherein

is selected from the group consisting of naphth-2-yl and8-fluoro-naphth-2-yl; R⁶ is hydrogen; R⁷ is hydrogen; Y is selected fromthe group consisting of —CH(isopropyl), —C(OH)(isopropyl)-,—CH(isopropyl)-CH₂— and —CH₂—CH(isopropyl)-; Z is selected from thegroup consisting of —C(O)—NH₂, —C(O)—NH(isopropyl), —C(O)—NH(OCH₃),—C(O)—NH(CH(CH₂OH)₂), —C(O)—NH(C(CH₂OH)₃), —C(O)—NH—CH₂CH₂OH,—C(O)—NH—CH₂CH₂O—CH₂CH₂—N(CH₃)₂,—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂—N(CH₃)₂,—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂O—CH₃, —NH—C(O)—NH₂, and—NH-(E)-C(NH₂)═N—CN; or a tautomer or a pharmaceutically acceptable saltthereof.
 8. A compound as in claim 4, wherein

is selected from the group consisting of naphth-2-yl and8-fluoro-naphth-2-yl; R⁶ is hydrogen; R⁷ is hydrogen; Y is selected fromthe group consisting of —CH(isopropyl), —C(OH)(isopropyl)- and—CH(isopropyl)-CH₂—; Z is selected from the group consisting of—C(O)—NH₂, —C(O)—NH(isopropyl), —C(O)—NH(OCH₃), —C(O)—NH(CH(CH₂OH)₂),—C(O)—NH—CH₂CH₂OH, —C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂O—CH₃, —NH—C(O)—NH₂,and —NH-(E)-C(NH₂)═N—CN; or a tautomer or a pharmaceutically acceptablesalt thereof.
 9. A compound as in claim 4, wherein

is selected from the group consisting of naphth-2-yl and8-fluoro-naphth-2-yl; R⁶ is hydrogen; R⁷ is hydrogen; Y is selected fromthe group consisting of —CH(isopropyl), and —CH(isopropyl)-CH₂—; Z isselected from the group consisting of —C(O)—NH₂, —C(O)—NH(isopropyl),—C(O)—NH(OCH₃), —C(O)—NH—CH₂CH₂OH and—C(O)—NH—CH₂CH₂O—CH₂CH₂O—CH₂CH₂O—CH₃; or a tautomer or apharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of claim
 1. 11. A pharmaceutical composition made by mixing acompound of claim 1 and a pharmaceutically acceptable carrier.
 12. Aprocess for making a pharmaceutical composition comprising mixing acompound of claim 1 and a pharmaceutically acceptable carrier.
 13. Amethod of antagonism of the EP3 receptor, comprising administering to asubject in need thereof a therapeutically effective amount of thecompound of claim
 1. 14. The method of claim 13, wherein the subject hasa disorder selected from the group consisting of Type I diabetesmellitus, impaired glucose tolerance (IGT), impaired fasting glucose(IFG), gestational diabetes, Type II diabetes mellitus, Syndrome X (alsoknown as Metabolic Syndrome), obesity, nephropathy, neuropathy,retinopathy, restenosis, thrombosis, coronary artery disease,hypertension, angina, atherosclerosis, heart disease, heart attack,ischemia, stroke, nerve damage or poor blood flow in the feet,neurodegenerative disorders, non-alcoholic steatohepatitis (NASH),non-alcoholic fatty liver disease (NAFLD), liver fibrosis, cataracts,polycystic ovarian syndrome, premature labor, irritable bowel syndrome,bladder over-activity, inflammation, pain and cancer.
 15. A method ofantagonism of the EP3 receptor comprising administering to a subject inneed thereof a therapeutically effective amount of the composition ofclaim
 10. 16. A method of treating a condition selected from the groupconsisting of Type I diabetes mellitus, impaired glucose tolerance(IGT), impaired fasting glucose (IFG), gestational diabetes, Type IIdiabetes mellitus, Syndrome X (also known as Metabolic Syndrome), andobesity comprising administering to a subject in need thereof, atherapeutically effective amount of the compound of claim 1.